In a recent review published within the journal Trends in Neurosciences, researchers examined the present evidence that emphasizes midlife as a critical period in brain aging, influencing cognitive trajectories and brain health. They recommend using models that account for non-linear changes across a large age range to tell apart between processes specific to midlife and those who occur uniformly throughout life.

Review: The ‘middle-aging’ brain. Image Credit: Monkey Business Images / Shutterstock

Background 

Middle age, spanning roughly 40 to 60–65 years, marks a transition to old age and predicts future health outcomes, including dementia risk. Nonetheless, it’s understudied in comparison with older age groups. Recent research reveals complex, non-linear biological aging processes, especially within the brain, during middle age. Further, gene expression and structural changes may predict cognitive decline accelerated by menopause in women. Understanding these processes could uncover latest biomarkers and interventions for cognitive decline. In the current review, researchers examined the evidence from human and animal studies at multiple levels of research. They discussed middle age as a crucial period in brain aging, which could potentially be prognostic of future cognitive health.

Cognitive changes within the middle-aged brain

The Baltimore Longitudinal Study of Aging suggests that cognitive decline in middle age follows diverse and non-linear patterns, particularly affecting memory, reasoning, and response time. Notably, episodic memory displays instability throughout the transition from middle to old age, possibly influenced by changing social dynamics and profession trajectories. Declines in processing speed also intensify during this era, with practice effects diminishing across the age of 60 years, potentially indicating early cognitive impairment. Genetic aspects, just like the apolipoprotein E (APOE) ε4 allele, may exacerbate memory decline in middle age. Neuroimaging studies reveal non-linear changes in hippocampal structure and performance, suggesting a transition point for cognitive decline emergence. These trends are mirrored in mouse studies, confirming the importance of middle age in cognitive trajectories.

Structural and functional changes

Middle age brings each linear and non-linear changes to the brain, with significant alterations in structures just like the hippocampus and white matter tracts occurring across the fifth to sixth many years. These changes affect cognitive functions, especially episodic memory, and are related to overall cognitive status. Functional connectivity of brain networks also undergoes non-linear trends, with declines in system segregation and lack of functional specialization. These alterations potentially explain individual differences in cognitive aging trajectories, highlighting the complex biological dynamics at play during middle age.

Cellular and molecular changes

Research into organismal aging has increasingly employed large-scale “omics” assays, revealing each linear and non-linear trajectories across various molecular processes. Biological “clocks” constructed from features like deoxyribonucleic acid (DNA) methylation predict chronological age, with some clocks exhibiting non-linear patterns. Molecular processes, including gene expression and non-coding ribonucleic acid (RNA) expression, also reveal non-linear changes, particularly during middle age. These changes, observed in pathways related to mTOR (short for mammalian goal of rapamycin), mitochondria, synapses, and inflammation, may underlie individual aging trajectories, highlighting the complex dynamics of aging. Moreover, brain changes during middle age can also be influenced by systemic aspects and other organs, suggesting a holistic approach to understanding aging processes.

Peripheral regulators of middle-aging of the brain

During middle age, significant changes occur outside the brain, particularly within the systemic circulation, involving inflammatory pathways. These changes influence cognitive aging trajectories and are predictive of cognitive decline and incident dementia later in life. Studies indicate that markers of inflammation and immune response in midlife predict cognitive decline and dementia onset as much as twenty years later. Moreover, shifts in peripheral metabolite levels during midlife, possibly influenced by gut microbiota composition, can also impact neuroinflammation and cognition. Importantly, the biological age of peripheral organs can influence brain aging, highlighting the interconnectedness of systemic and cognitive aging processes during middle age.

Menopause and feminine middle age

Menopause, occurring across the age of fifty years in females, accelerates epigenetic aging and affects cognition, with variations amongst individuals. The transition to menopause is related to cognitive declines, particularly in verbal episodic memory, together with changes in hippocampal volume, brain metabolism, and white matter integrity. Early menopause correlates with faster brain aging, possibly influenced by hormonal shifts. Hormonal fluctuations throughout the menstrual cycle also impact hippocampal volume. Studies in rats suggest menopause influences hippocampal pathways and immune response. Menopause likely serves as a breakpoint in various brain aging processes, although its effects vary across species. Overall, menopause is a vital aspect of midlife, deserving further exploration in brain aging research.

Conclusion

In conclusion, middle-age is characterised by unique biological processes influencing the long run brain and cognitive health. Complex trajectories in brain connectivity, gene expression, and systemic aspects highlight the importance of longitudinal studies for improving our understanding of those processes. Promising interventions, equivalent to exercise, offer avenues for mitigating cognitive decline. Sex differences observed in aging processes highlight the necessity for inclusive research approaches. Non-linear evaluation methods, alongside broad age range studies, could help differentiate middle-age-specific changes from lifelong aging markers, offering insights into brain aging and cognitive health in an aging population.