White matter lipid alterations during aging in the rhesus monkey brain.

The brain of higher organisms, such as nonhuman primates, is particularly rich in lipids, with a gray to white matter ratio of approximately 40 to 60%. White matter primarily consists of lipids, and during normal aging, it undergoes significant degeneration due to myelin pathology, which includes structural abnormalities, like sheath splitting, and local inflammation. Cognitive decline in normal aging, without neurodegenerative diseases, is strongly linked to myelin pathology. Although the exact cause of myelin damage is unclear, older myelin differs from younger myelin, as shown by electron microscopy and altered expression of myelin-related RNAs. However, changes in lipid composition during brain aging remain poorly understood. This study assessed lipid profiles from the frontal lobe corpus callosum, an area where age-related myelin pathology is linked to cognitive decline. Results showed significant changes in lipids with age, revealing distinct age-related profiles. Some lipids that are enriched in myelin sheaths become more saturated, while important structural components, like ceramides, decrease. Disease-associated biomarkers such as cholesterol ester Che (22:6) and sulfatide ST (42:2) also change in older monkeys. Additionally, gene expression of lipid biosynthetic enzymes declines with age, while lipid peroxidation remains stable in the same brain region. This suggests that changes in lipid biosynthesis, rather than oxidative damage, likely account for the differences in lipid composition. Our findings indicate that myelin in the normal aging monkey brain shows diverse lipid changes, which may relate to age-related myelin pathology and could constitute targets for designing nutrient supplements or drugs to rejuvenate the brain's lipidome.

Immune proteins C1q and CD47 may contribute to aberrant microglia-mediated synapse loss in the aging monkey brain that is associated with cognitive impairment.

Cognitive impairment in learning, memory, and executive function occurs in normal aging even in the absence of Alzheimer's disease (AD). While neurons do not degenerate in humans or monkeys free of AD, there are structural changes including synapse loss and dendritic atrophy, especially in the dorsolateral prefrontal cortex (dlPFC), and these correlate with cognitive age-related impairment. Developmental studies revealed activity-dependent neuronal properties that lead to synapse remodeling by microglia. Microglia-mediated phagocytosis that may eliminate synapses is regulated by immune "eat me" and "don't eat me" signaling proteins in an activity-dependent manner, so that less active synapses are eliminated. Whether this process contributes to age-related synapse loss remains unknown. The present study used a rhesus monkey model of normal aging to investigate the balance between the "eat me" signal, complement component C1q, and the "don't eat me" signal, transmembrane glycoprotein CD47, relative to age-related synapse loss in dlPFC Area 46. Results showed an age-related elevation of C1q and reduction of CD47 at PSD95+ synapses that is associated with cognitive impairment. Additionally, reduced neuronal CD47 RNA expression was found, indicating that aged neurons were less able to produce the protective signal CD47. Interestingly, microglia do not show the hypertrophic morphology indicative of phagocytic activity. These findings suggest that in the aging brain, changes in the balance of immunologic proteins give microglia instructions favoring synapse elimination of less active synapses, but this may occur by a process other than classic phagocytosis such as trogocytosis.

Potential trade-off between olfactory and visual discrimination learning in common marmosets (Callithrix jacchus): Implications for the assessment of age-related cognitive decline.

Olfactory dysfunction has been identified as an early biomarker for dementia risk but has rarely been assessed in nonhuman primate models of human aging. To better characterize common marmosets as such models, we assessed olfactory discrimination performance in a sample of 10 animals (5 females), aged 2.5-8.9 years old. The monkeys were proficient in the discrimination and reversal of visual stimuli but naïve to odor stimuli. For olfactory discrimination, the monkeys performed a series of six discriminations of increasing difficulty between two odor stimuli. We found no evidence for an age-related decline as both young and older individuals were able to perform the discriminations in roughly the same number of trials. In addition, the older monkeys had faster responses than the younger animals. However, we noted that when adjusted for age, the speed of acquisition of the first discrimination in the olfactory modality was inversely correlated to the speed of acquisition of their first discrimination of two visual stimuli months earlier. These results suggest that marmosets may compensate for sensory deficits in one modality with higher sensory performance in another. These data have broad implications for the assessment of age-related cognitive decline and the categorization of animals as impaired or nonimpaired.