Aging brain

About: Aging brain is a research topic. Over the lifetime, 1255 publications have been published within this topic receiving 66405 citations.

What we can learn from animal models about cerebral multi-morbidity

Abstract: Late-onset diseases such as Alzheimer’s disease, Parkinson’s disease, or frontotemporal lobar degeneration are considered to be protein-folding disorders, with the accumulation of protein deposits causing a gain-of-toxic function. Alzheimer’s disease is characterized by two histological hallmark lesions: amyloid-β-containing plaques and tau-containing neurofibrillary tangles. However, signature proteins, including α-synuclein, which are found in an aggregated fibrillar form in the Lewy bodies of Parkinson’s disease brains, are also frequently found in Alzheimer’s disease. This highlights the fact that, although specific aggregates form the basis for diagnosis, there is a high prevalence of clinical overlap between neuropathological lesions linked to different diseases, a finding known as cerebral co- or multi-morbidity. Furthermore, the proteins forming these lesions interact, and this interaction accelerates an ongoing degenerative process. Here, we review the contribution that transgenic animal models have made to a better mechanistic understanding of the causes and consequences of co- or multi-morbidity. We discuss selected vertebrate and invertebrate models as well as the insight gained from non-transgenic senescence-accelerated mouse-prone mice. This article is part of a series on ‘Cerebral multi-morbidity of the aging brain’.

Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction

Abstract: Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the lifespan. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology. Specifically, infusion of the serum protein albumin into the young brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors, or pharmacological inhibition of TGFβ signaling, reversed these symptomatic outcomes in aged mice. Finally, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging, and demonstrates that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition of TGFβ signaling.

A chemical biology approach to identifying molecular pathways associated with aging

Abstract: The understanding of how aging contributes to dementia remains obscure. To address this problem, a chemical biology approach was used employing CAD031, an Alzheimer's disease (AD) drug candidate identified using a discovery platform based upon phenotypic screens that mimic toxicities associated with the aging brain. Since CAD031 has therapeutic efficacy when fed to old symptomatic transgenic AD mice, the chemical biology hypothesis is that it can be used to determine the molecular pathways associated with age-related disease by identifying those that are modified by the compound. Here we show that when CAD031 was fed to rapidly aging SAMP8 mice starting in the last quadrant of their lifespan, it reduced many of the changes in gene, protein, and small molecule expression associated with mitochondrial aging, maintaining mitochondria at the younger molecular phenotype. Network analysis integrating the metabolomics and transcription data followed by mechanistic validation showed that CAD031 targets acetyl-CoA and fatty acid metabolism via the AMPK/ACC1 pathway. Importantly, CAD031 extended the median lifespan of SAMP8 mice by about 30%. These data show that specific alterations in mitochondrial composition and metabolism highly correlate with aging, supporting the use AD drug candidates that limit physiological aging in the brain.

Morphological changes of aging brain structure in MRI analysis

Abstract: The human brain atrophies with aging. By investigating the morphological change of brain structure and comparing with the deformation of normal aging, we can diagnose the cerebral diseases such as Alzheimer's diseases, Perkinson disease, etc. Magnetic resonance imaging (MRI) is a good diagnostic tool because it is non-invasive to the human body, and it can take the thin-sectional images with high contrast. This paper shows a method to investigate the morphological structure of the human brain using MRI. The method segments the brain region, liner and non-liner registration to a standard brain, and inverse wrapping from the standard brain. By giving some landmarks to the standard brain, we can obtain the landmark position of each subject. We investigate the morphological change using the position changes. The method has been applied to open database (IXI dataset) that contains 619 subjects whose age is 19.98–83.62 years old.

Oxidative Stress and the Brain: An Insight into Cognitive Aging

Abstract: The last two decades has witnessed accumulating evidences in favour of oxidative stress as a causative link between normal brain aging and several neuropathological conditions. Reactive oxygen species (ROS) is considered a major factor contributing to decline in brain function with aging. Cognitive impairment and oxidative stress are common occurrences in old age and are often traceable to events such as increased lipid peroxidation and protein oxidations in specific cognitive regions of the brain, the hippocampus and cerebral cortex. With the advent of various cognitive tests, oxidative pathology is further confirmed by behavioural changes in animal and humans as well. While much of the biomedical research is concentrating on methods to cure aging related neurodegeneration and cognitive decline, biogerontologists are seeking something larger with a view to finding ways to prevent it at its root. Here we discuss and highlight the possibilities of curtailing the cognitive deficits during normal and pathological aging through evidences in favour of vitamin and non-vitamin supplements—in an effort to run the biological clock backwards and extend healthy brain function.