Integrated multi-omics analysis of brain aging in female nonhuman primates reveals altered signaling pathways relevant to age-related disorders

Cox, Laura A.; Puppala, Sobha; Chan, Jeannie; Zimmerman, Kip D.; Hamid, Zeeshan; Ampong, Isaac; Huber, Hillary F.; Li, Ge; Jadhav, Avinash Y.L.; Wang, Benlian; Li, Cun; Baxter, Mark G.; Shively, Carol; Clarke, Geoffrey D.; Register, Thomas C.; Nathanielsz, Peter W.; Olivier, Michael

doi:10.1016/j.neurobiolaging.2023.08.009

Cited by 5 publications

(1 citation statement)

References 73 publications

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“…The baboons were part of a cohort of animals studied throughout the life course to identify and establish effects of physiological aging [10,[12][13]. All sample collections for primary cell cultures were taken opportunistically at prescribed euthanasia for animals in this larger study.…”

Section: Animalsmentioning

confidence: 99%

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons

Adekunbi,

Huber,

et al. 2024

Preprint

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Biological resilience, broadly defined as ability to recover from acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3-17.8 years spanning across different tissues, tissue regions, and cell types including: (1) fibroblasts from skin and from heart separated into left ventricle (LV), right ventricle (RV), left atrium (LA) and right atrium (RA), (2) astrocytes from the prefrontal cortex and hippocampus and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50uM-H2O2), metabolic (1mM-glucose) and proteostasis (0.1uM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor specific. For example, astrocytes were more energetic and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to age and developmental status of donors as potential predictive markers.

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Section: Animalsmentioning

confidence: 99%

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons

Adekunbi,

Huber,

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons

Adekunbi,

Huber,

et al. 2024

GeroScience

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Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment

Gawryluk,

Cybulska-Klosowicz,

Charzynska

et al. 2024

Sci Rep

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Aging-related biochemical changes in nerve cells lead to dysfunctional synapses and disrupted neuronal circuits, ultimately affecting vital processes such as brain plasticity, learning, and memory. The imbalance between excitation and inhibition in synaptic function during aging contributes to cognitive impairment, emphasizing the importance of compensatory mechanisms. Fear conditioningrelated plasticity of the somatosensory barrel cortex, relying on the proper functioning and extensive up regulation of the GABAergic system, in particular interneurons containing somatostatin, is compromised in aging (one-year-old) mice. The present research explores two potential interventions, taurine supplementation, and environmental enrichment, revealing their effectiveness in supporting learning-induced plasticity in the aging mouse brain. They do not act through a mechanism normalizing the Glutamate/GABA balance that is disrupted in aging. Still, they allow for increased somatostatin levels, an effect observed in young animals after learning. These findings highlight the potential of lifestyle interventions and diet supplementation to mitigate age-related cognitive decline by promoting experience-dependent plasticity.Aging-related biochemical alterations in nerve cells lead to malfunctioning synapses and, consequently, entire neuronal circuits, adversely affecting their functioning, including such vital processes as brain plasticity, learning, and memory. Along with the reduced release of neurotransmitters and decreased neuronal reactivity observed in aging, a decrease in the number of neurons and their synaptic contacts can cause a loss of balance between excitation and inhibition (E/I), leading to impaired plasticity. If compensatory mechanisms are ineffective, this can cause cognitive impairment and even activate biochemical pathways, leading to various pathological conditions. E/I imbalance is, however, also observed in physiological aging of the nervous system when it is associated with impaired plasticity and reduced cognitive potential. The direction of E/I changes may vary depending on the brain area studied. In the prefrontal cortex, available experimental data support an increase in inhibition with age, correlating with memory deficits 1-5 , while evidence of decreased inhibition was found in the sensory systems and hippocampus 6 . In the rat parietal cortex, an imbalance of arousal/inhibition in favor of inhibition correlated with cognitive impairment 7 . These data indicate that in aging, cognitive performance is affected by changes in the E/I balance at the synapse.We have confirmed this hypothesis, showing a reduction in the glutamate/GABA ratio in the somatosensory cortex of aging mice, which was associated with impaired learning-dependent neuroplasticity 8 . Plasticity of cortical maps induced by fear-conditioning, in which a tactile stimulus applied to the vibrissae is paired with a mild electric aversive stimulus to the tail, requires a strong response from the GABAergic system 9-12 . The same conditioning...

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Integrated multi-omics analysis of brain aging in female nonhuman primates reveals altered signaling pathways relevant to age-related disorders

Cited by 5 publications

References 73 publications

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons

Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment

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