Pathways toward and away from a metabolic cliff during brain aging
Year: 2025
Type: article
Abstract: Aging manifests as an inexorable decline in the function of all organ systems owing to dysregulation of, and damage, to their cellular components. Scientists have identified numerous alterations that occur in cells throughout the body and brain during aging. These include: genomic instability; oxidative damage to DNA, proteins, and cell membranes; the accumulation of aggregated proteins and dysfunctional mitochondria; impaired ability of cells to repair molecular damage; impaired autophagy; and decrements in signaling pathways that normally bolster a cell's ability to cope with stress (Lopez-Otin et al., 2023). These aging processes render humans vulnerable to a range of diseases, including cancers, diabetes, cardiovascular disease, neurodegenerative disorders, and infections by viruses and bacteria.Similar to the decline of physical capabilities, the performance of the human brain begins to decline during the third and fourth decades of life. Importantly, many people develop a catastrophic neurodegenerative disorder such as Alzheimer's disease (AD) or Parkinson's disease (PD) when they are in their 70s and 80s. In fact, by the age of 85 around half all people will have one of these brain disorders. Neurons in the brain are particularly vulnerable to dysfunction and degeneration during aging, in part because their electrical activity generates high levels of oxidative and metabolic stress. The brain consists of complex networks of hundreds of billions of neurons, glial cells, and blood vessels that must communicate with each other in a highly integrated manner to support the energy requirements and functions of this organ. There is a tight coupling of neuron activity and blood flow, with glial cells serving an intermediary role in this process (Iadecola, 2017).While these complexities pose a major challenge for the brain during aging it is unclear how energy metabolism becomes disrupted during aging, and if and how this disruption contributes to functional decline or susceptibility to AD and PD.Polina Shichkova, Henry Markram, and colleagues tapped publicly available databases and used sophisticated modeling methods to tackle the complicated problem of energy metabolism and brain aging (Shichkova et al., 2025). They performed a large-scale analysis of nearly 17,000 interactive biochemical pathways involved in regulating neuronal excitability, energy metabolism, and neuron-glia-blood vessel coupling during brain aging in humans. Their analyses included all nutrient and ion transporters, enzymatic pathways, and intercellular signaling pathways critical for neural network activity. Importantly, they also modeled these metabolic factors in both active (firing) and resting neurons. There were numerous novel findings, many of which can only be appreciated by a thorough interrogation of the data and the authors' discussion of their results. Here I highlight several of their major findings and their implications.A comparison of the interaction networks from young and old brains revealed a novel and very interesting general effect of aging. In the young brain the impact of one pathway on all other pathways is evenly distributed, whereas in the old brain interaction pathways exhibit clustering. The authors interpret this to mean that brain metabolism is more robust in the young brain because it has ways of adapting to physiological challenges such as stress or physical exercise (i.e., greater flexibility). A decline in metabolic flexibility during aging is consistent with evidence for age-related brain insulin resistance and impaired neuronal glucose utilization (Frazier et al., 2019). In addition to revealing the consequences of aging on brain metabolic pathways and their impact on the control of neuronal network activity, the findings of Shichkova et al. may explain why stress resilience and recovery from traumatic brain injury or stroke are generally better in young people than in old people (Bigler and Stern, 2015).
Source: Frontiers in Science
Author: Mark P. Mattson
Institutions: Johns Hopkins University, Johns Hopkins Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4408807453