A recent study published in the Proceedings of the National Academy of Sciences (PNAS) highlights a distinct pattern in brain aging, offering insights into when interventions might be most effective to prevent cognitive decline. The research, led by Lilianne R. Mujica-Parodi from Stony Brook University, involved an international team of scientists who analyzed data from over 19,300 individuals across four large-scale datasets.
The study found that brain networks degrade following an S-shaped statistical curve with clear transition points. These changes begin around age 44, peak at age 67, and plateau by age 90. This contradicts previous assumptions of either a late-life clinical onset or a gradual linear decline. Nathan Smith's prior work had indicated that hypometabolism affects brain signaling, suggesting specific windows for intervention.
“Understanding exactly when and how brain aging accelerates gives us strategic timepoints for intervention,” said Mujica-Parodi. She explained that there is a critical midlife window where neurons are metabolically stressed but still viable. Providing alternative fuel during this period could restore function before irreversible damage occurs.
The researchers identified neuronal insulin resistance as the primary driver of this trajectory. Metabolic changes were found to precede vascular and inflammatory ones, with gene expression analyses implicating GLUT4 and APOE in these patterns. However, MCT2 was identified as a potential protective factor, suggesting benefits from enhancing the brain’s ability to use ketones.
An interventional study compared glucose and ketone administration among 101 participants at different stages of aging. Ketones stabilized deteriorating brain networks more effectively than glucose but varied across transition points. Maximum benefits were seen during midlife metabolic stress (ages 40-59), while older adults (ages 60-79) experienced diminished effects due to compounding vascular issues.
Mujica-Parodi emphasized that these findings could change approaches to preventing cognitive decline and diseases like Alzheimer’s: “This represents a paradigm shift in how we think about brain aging prevention,” said Botond Antal, first author and postdoctoral associate at Stony Brook University.
These insights could lead to new screening guidelines and preventive measures by identifying increasing insulin resistance in the brain early on and applying targeted metabolic interventions.
The research was supported by the W.M. Keck Foundation and the National Science Foundation Brain Research through Advancing Neurotechnologies initiative, with contributions from institutions including Massachusetts General Hospital, Mayo Clinic, Oxford University, and Memorial Sloan Kettering.