Memory Maintained in Aged Monkeys When Treated with Curcumin in Midlife
Although we wear many age-related changes on the outside, like gray hair and wrinkles, the changes occurring inside can profoundly affect life experience. For example, working memory loss, which allows us to work with information without losing track of what we're doing, can be devastating. From forgetting the steps of a recipe while cooking to the directions to a destination while driving, working memory loss breaks up the story of our lives.
A new study published in the Neurobiology of Aging shows that the potent antioxidant curcumin, often associated with the orange ginger-like plant turmeric, can support working memory during aging. Researchers from the Boston University School of Medicine show that middle-aged monkeys given dietary curcumin exhibited better working memory performance and less neuron excitability — the ability to activate and communicate — compared to untreated subjects. This study suggests that the appropriate time frame for intervention for age-related cognitive changes is early middle age and points to the efficacy of curcumin in supporting working memory.
Age-related impairments in working memory begin in middle age
Age-related cognitive decline in a significant proportion of humans and nonhuman primates has been well documented. Higher-order cognitive functions like flexible thinking, working memory, and self-control mediated by the left prefrontal cortex (LPFC) are especially vulnerable compared to sensory functions like visual discrimination — the ability to detect differences in and ability to classify objects, symbols, or shapes. There is growing evidence that declines in LPFC-mediated functions like working memory begin in people and non-human primates during early middle age.
We don’t fully understand what’s behind the age-dependent decline in working memory abilities. There’s an array of possibilities, from sublethal changes to neurons that comprise the circuits in the LPFC and associated brain structures leading to alterations in the electrical patterns and communication between neurons — the brain cells that transmit information — required for working memory. In this article, Chang and colleagues observe that specific brain neurons’ electrical properties, shape, and size begin to change in middle age.
Changes to the form and functionality of working memory neurons begins in middle age
Chang and colleagues looked into the temporal progression of age-related changes to working memory performance of rhesus monkeys across the adult lifespan — between 5.5 and 29.5 years of age. They found that these non-human primates demonstrate a continuous decline of spatial working memory over the aging process beginning in early middle age.
With the loss of working memory, the Boston University School of Medicine researchers examined if the underlying changes to the structure and function of neurons occur at a similar time point during the aging process. There were several signs of altered excitability of neurons across the adult lifespan in these monkeys, including significantly elevated firing frequency in LPFC cells called pyramidal neurons, which are named for the triangular surfaces of their cell bodies.
Also, these pyramidal neurons began to look different with age. For example, there was a modest reduction in the total length of the apical dendrites — a structure protruding from the pyramidal neurons’ apex that receives electrical signals from other neurons — with aging. There were dramatic age-related reductions of dendritic spines in dendritic compartments. Dendritic spines are major sites of excitatory synapses, and the density of excitatory synapses in the LPFC is significantly negatively correlated with age over the adult lifespan of rhesus monkeys. Chang and colleagues think that the reduced spine number and altered excitability are likely underlying the reported reduction in the persistent activity of these neurons during working memory tasks by aged monkeys.
Dietary curcumin ameliorates age-related changes to working memory
As a powerful antioxidant and anti-inflammatory agent, curcumin has been demonstrated to exert many cellular effects that may benefit cognitive function. Rhesus monkeys that received dietary curcumin exhibited significantly greater improvements in both spatial and object working memory performance over consecutive testing rounds. What’s more, curcumin administration reduced alterations to the excitability of middle-aged and aged neurons. It would thus be tempting to speculate that the beneficial effect of curcumin on working memory performance may be due to its ability to affect neuronal excitability by some unknown mechanism.
“We replicated previous reports of changes to neuronal properties and working memory function in aged animals and demonstrated that the onset of the most significant changes — hyperexcitability, spine loss, and working memory impairment — occurs relatively early in the aging process during middle age,” concluded Chang and colleagues. “Furthermore, we showed that dietary curcumin improves working memory performance and also prevents the age-associated increase in evoked firing rates of neurons.”
The question arises as to how curcumin ameliorates age-related working memory deficits. As a powerful antioxidant and anti-inflammatory agent, curcumin has been demonstrated to exert many cellular effects that may benefit cognitive function. For example, curcumin enhances beneficial autophagy — the recycling and cleanup of damaged cell components — in the brain. It also increases cellular energy production, which may be required for persistent firing of neurons during the delay periods in working memory.
Although the action of curcumin on inflammation and oxidative stress on peripheral organ systems is well known, the effect on the brain is not well understood. Indeed, although Chang and colleagues used a version of curcumin shown to cross the blood-brain barrier, whether curcumin was metabolized in the brains of monkeys in this cohort is unknown. Future work is needed to assess the dynamics of curcumin absorption. It will also be important to test the efficacy of curcumin in aged animals, where inflammation and oxidative stress are more severe, and in monkeys from middle to old age to see if curcumin can prevent the progression of age-related inflammation and neuronal activity dysfunction.
Chang W, Weaver CM, Medalla M, Moore TL, Luebke JI. Age-related alterations to working memory and to pyramidal neurons in the prefrontal cortex of rhesus monkeys begin in early middle-age and are partially ameliorated by dietary curcumin. Neurobiol Aging. 2021;109:113-124. doi:10.1016/j.neurobiolaging.2021.09.012