More of Brain Aging Than Thought May Be Vascular in Nature

Age-related deterioration in blood vessels and the broader cardiovascular system generates damage in the brain. Blood vessel walls are elastic, a property that depends on the molecular structure of the proteins making up the extracellular matrix in that tissue. This structure is progressively degraded by the presence of sugary metabolic waste known as advanced glycation end-products (AGEs), which leads to the formation of cross-links between proteins and a consequent loss of elasticity. Stiffening of blood vessels causes hypertension and many of the cellular and molecular mechanisms involved overlap with those that speed the progression of atherosclerosis, a condition in which blood vessel walls become sources of chronic inflammation and are remodeled into fatty deposits by abnormal cellular activity. All of this causes a rising number of structural failures in the small blood vessels of the brain. Each one is effectively a tiny, unnoticed stroke, killing cells in a minuscule area of the brain. This harm adds up over time and is one of the contributing causes of age-related cognitive impairment.

A recently published paper suggests that more of the age-related changes observed in the brain may be due to vascular degeneration than previously thought. If so this implies that research aimed at removing cross-links has a greater importance, as do efforts to block the very early causes of atherosclerosis, such as the generation of oxidized lipids due to mitochondrial DNA damage. It also places a greater value on the basics of cardiovascular health in general: fitness, exercise, resilience, and so forth. When it comes to longevity and medicine, we must protect the brain: all other parts of the body could, in theory, be completely rebuilt or replaced if that becomes necessary, but the structure of the brain is the structure of the self. Lose that and there is nothing that can be done. Retain it and even if you must be cryopreserved as a last resort, there is still a chance at a future.

Human brains age less than previously thought

Older brains may be more similar to younger brains than previously thought. Researchers have demonstrated that previously reported changes in the ageing brain using functional magnetic resonance imaging (fMRI) may be due to vascular (or blood vessels) changes, rather than changes in neuronal activity itself. Given the large number of fMRI studies used to assess the ageing brain, this has important consequences for understanding how the brain changes with age and challenges current theories of ageing. A fundamental problem of fMRI is that it measures neural activity indirectly through changes in regional blood flow. Thus, without careful correction for age differences in vasculature reactivity, differences in fMRI signals can be erroneously regarded as neuronal differences. An important line of research focuses on controlling for noise in fMRI signals using additional baseline measures of vascular function. However, such methods have not been widely used, possibly because they are impractical to implement in studies of ageing.

An alternative candidate for correction makes use of resting state fMRI measurements, which is easy to acquire in most fMRI experiments. While this method has been difficult to validate in the past, the unique combination of an impressive data set across 335 healthy volunteers over the lifespan, as part of the CamCAN project, allowed researchers to probe the true nature of ageing effects on resting state fMRI signal amplitude. Their research showed that age differences in signal amplitude during a task are of a vascular, not neuronal, origin.

The effect of ageing on fMRI: Correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults

In functional magnetic resonance imaging (fMRI) research one is typically interested in neural activity. However, the blood-oxygenation level-dependent (BOLD) signal is a composite of both neural and vascular activity. As factors such as age or medication may alter vascular function, it is essential to account for changes in neurovascular coupling when investigating neurocognitive functioning with fMRI. The resting-state fluctuation amplitude (RSFA) in the fMRI signal has been proposed as an index of vascular reactivity.

The use of RSFA is predicated on its sensitivity to vascular rather than neural factors. The effects of ageing on RSFA were significantly mediated by vascular factors, but importantly not by the variability in neuronal activity. The scaling analysis revealed that much of the effects of age on task-based activation studies with fMRI do not survive correction for changes in vascular reactivity, and are likely to have been overestimated in previous fMRI studies of ageing.


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