As mice age, those treated with J147 (right) showed improved physiology, memory and appearance that more closely resembled younger mice (credit: the Salk Institute for Biological Studies)
Salk Institute researchers have found that an experimental drug candidate called called J147, which was aimed at combating Alzheimer’s disease, also has a host of unexpected anti-aging effects in animals.
The team used a mouse model of aging not typically used in Alzheimer’s research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain, and other improved physiological features, as detailed Nov. 12 in an open-access paper in the journal Aging.
The researchers used a comprehensive set of assays to measure the expression of all genes in the brain, along with 500 small molecules involved with metabolism in the brains and blood of three groups of the rapidly aging mice. The three groups included one set that was young, one set that was old, and one set that was old but fed J147 as they aged.
The old mice that received J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer’s in their brains. Importantly, because of the large amount of data collected on the three groups of mice, it was possible to demonstrate that many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of young animals. These included markers for increased energy metabolism, reduced brain inflammation, and reduced levels of oxidized fatty acids in the brain.
Another notable effect was that J147 prevented the leakage of blood from the microvessels in the brains of old mice. “Damaged blood vessels are a common feature of aging in general, and in Alzheimer’s, it is frequently much worse,” says Antonio Currais, the lead author and a member of Professor David Schubert’s Cellular Neurobiology Laboratory at Salk.
The team aims to begin human trials of J147 next year.
Alzheimer’s disease is a progressive brain disorder, recently ranked as the third leading cause of death in the United States and affecting more than five million Americans. It is also the most common cause of dementia in older adults, according to the National Institutes of Health. While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), few have proven effective in the clinic.
Abstract of A comprehensive multiomics approach toward understanding the relationship between aging and dementia
Because age is the greatest risk factor for sporadic Alzheimer’s disease (AD), phenotypic screens based upon old age-associated brain toxicities were used to develop the potent neurotrophic drug J147. Since certain aspects of aging may be primary cause of AD, we hypothesized that J147 would be effective against AD-associated pathology in rapidly aging SAMP8 mice and could be used to identify some of the molecular contributions of aging to AD. An inclusive and integrative multiomics approach was used to investigate protein and gene expression, metabolite levels, and cognition in old and young SAMP8 mice. J147 reduced cognitive deficits in old SAMP8 mice, while restoring multiple molecular markers associated with human AD, vascular pathology, impaired synaptic function, and inflammation to those approaching the young phenotype. The extensive assays used in this study identified a subset of molecular changes associated with aging that may be necessary for the development of AD.