Long-term calorie restriction may slow biological aging in the brain

A new study suggests that restricting calorie intake over a lifetime may slow the biological aging of support cells in the primate brain. The research provides evidence that a thirty percent reduction in calories preserves the metabolic function of cells responsible for insulating nerve fibers. These findings were published in the journal Aging Cell.

The brain relies on complex networks of communication to function correctly. This communication depends heavily on white matter, which consists of nerve fibers coated in a protective fatty substance called myelin. As primates age, this white matter tends to degrade. The loss of integrity in these areas often correlates with cognitive decline and slower processing speeds.

Scientists have sought to understand the cellular mechanisms that drive this age-related deterioration. Much of the focus has shifted toward glial cells, which were once considered merely supportive glue for neurons. It is now understood that glial cells, specifically oligodendrocytes and microglia, actively maintain brain health. Oligodendrocytes produce myelin, while microglia act as the brain’s immune system.

When these cells malfunction due to aging, they may contribute to the breakdown of white matter. Previous research in rodents has indicated that reducing calorie intake can extend lifespan and delay age-related diseases. However, it remains less clear how such interventions affect the complex brains of higher primates.

To investigate this, a team of researchers examined the effects of long-term calorie restriction on the rhesus monkey brain. The rhesus monkey serves as a robust model for human aging due to similarities in brain structure and cognitive decline patterns. The study utilized brain tissue from animals involved in a long-running project by the National Institute on Aging.

Free daily newsletter

The research was led by Ana T. Vitantonio and Tara L. Moore from the Boston University Chobanian & Avedisian School of Medicine, alongside colleagues from the National Institutes of Health. They aimed to determine if a diet with thirty percent fewer calories could alter the gene expression profiles of aging glial cells. The study compared these profiles against those of monkeys fed a standard diet.

The researchers analyzed brain tissue from the anterior corpus callosum, a region dense with white matter. They employed a technique called single nuclei RNA sequencing. This method allowed the team to identify which genes were active in thousands of individual cells. The primary sequencing dataset included samples from ten male rhesus monkeys.

The subjects ranged in age from 22 to 34 years, which is considered old for this species. Some animals had been on a calorie-restricted diet for over two decades. Others had consumed a standard diet for the same duration. The researchers also validated their findings using microscope imaging techniques on tissue from fourteen male and female monkeys.

The analysis revealed that while the total number of glial cells remained similar between groups, their internal molecular operations differed significantly. Oligodendrocytes from the calorie-restricted group showed signs of better metabolic health. These cells expressed higher levels of genes involved in glycolysis and fatty acid biosynthesis.

These pathways are essential for generating energy and creating the lipids required to maintain the myelin sheath. In contrast, oligodendrocytes from the control group exhibited gene signatures associated with stress and immune activation. This suggests that a standard diet may leave these cells more vulnerable to the wear and tear of aging.

The study also identified a specific subpopulation of oligodendrocytes that appeared to be specialized for interacting with nerve axons. The researchers termed these “synaptic” oligodendrocytes. In the calorie-restricted animals, this group of cells upregulated a gene called NLGN1. This gene codes for a protein that helps form physical connections between cells.

To confirm this genetic finding, the researchers used imaging to look at the physical position of these cells in the brain tissue. They found that oligodendrocytes expressing NLGN1 were located significantly closer to nerve axons. This proximity may facilitate better communication and metabolic support between the myelin-producing cells and the nerves they insulate.

The researchers also examined microglia, the immune cells that patrol the brain for damage. Microglia in the calorie-restricted group showed gene expression patterns linked to protein synthesis and metabolism. Conversely, microglia in the control group showed elevated signs of inflammation and oxidative stress.

A notable discovery involved a specific subset of microglia that appeared to be filled with myelin debris. These cells expressed genes suggesting they had engulfed damaged myelin but failed to process it effectively. The accumulation of such cells is often seen in neurodegenerative conditions. The study found that calorie-restricted monkeys had a significantly lower abundance of these debris-filled microglia.

This reduction implies that calorie restriction might either prevent myelin damage from occurring or improve the microglia’s ability to clear waste. The control group, having more of these cells, displayed a higher burden of tissue pathology. This distinction highlights a potential mechanism by which diet influences neuroinflammation.

In addition to analyzing resident brain cells, the team looked for immune cells that had infiltrated from the rest of the body. T cells are immune cells that typically reside in the blood but can enter the brain during aging or disease. The presence of T cells in the brain parenchyma is generally considered a sign of compromised health.

The study quantified the density of T cells in the white matter. The researchers found that while the total density did not differ significantly between the two groups, the relationship with age did. In control animals, T cell numbers tended to increase more steeply with age. The calorie-restricted group showed a slower rate of T cell accumulation over time.

This trend suggests that a lower calorie diet might mitigate the age-associated breakdown of the brain’s protective barriers. It may also reflect a general reduction in systemic inflammation. The findings provide evidence that the protective effects of calorie restriction extend to the cellular environment of the primate brain.

There are some limitations to the study. The primary genetic sequencing was conducted only on male subjects due to tissue availability. Although validation experiments included females, sex-specific differences in response to diet remain an area for further exploration. Additionally, the sample size was relatively small, which is common in studies involving non-human primates.

The study is observational and relies on post-mortem tissue. This means the researchers captured a snapshot of the cellular state rather than observing the process in real time. Consequently, the study identifies associations rather than definitive causal mechanisms. Future research will need to uncover the precise molecular signals that link diet to these changes in gene expression.

Despite these limitations, the research offers a detailed view of how lifestyle interventions may influence brain aging at the transcriptomic level. It suggests that the metabolic reprogramming of glial cells is a viable target for maintaining white matter health. The findings reinforce the potential of dietary strategies to promote resilience in the aging brain.

The study, “Calorie Restriction Attenuates Transcriptional Aging Signatures in White Matter Oligodendrocytes and Immune Cells of the Monkey Brain,” was authored by Ana T. Vitantonio, Christina Dimovasili, Yuchen Liu, Bingtian Ye, Jou-Hsuan Roxie Lee, Molly Hartigan, Benjamin Bouchard, Madelyn Ray, Bryce Conner, Kelli L. Vaughan, Julie A. Mattison, Tara L. Moore, Chao Zhang, and Douglas L. Rosene.