The declining mind

We all know that as we age our minds, like the rest of our body, begins to show signs of decline.

At first we notice that we don't have the same vocabulary (we just can't find the word we want to use), we find it difficult to learn new skills and then we can't perform the same mental gymnastics we did when we were younger. Eventually, we start to forget things from our past. Alzheimer's and Parkinson's disease along with dementia stalk the elderly. However, researchers at UC San Francisco have come up with another possible reason for our decline. They have identified the build-up of one brain chemical as a key culprit behind age-related learning and memory impairments.

It's a fact of life, for lifeforms big and small, that the mind declines with age. And that can be useful when you want to test new theories behind the chemistry of ageing. During the last three decades the soil nematode Caenorhabditis elegans has become a prominent model organism for studying aging. Two key benefits of using this model is relative short-lived and takes up modest lab space. Initially research in the C. elegans aging field was focused on the genetics of aging and single gene mutations that dramatically increased the life span of the worm. Undoubtedly, the existence of such mutations is one of the main reasons for the popularity of the worm as a model in which we can study aging. However, today many different approaches are being used in the C. elegans aging field in addition to genetic manipulations that influence life span. For example, environmental manipulations such as caloric restriction and hormetic treatments, evolutionary studies, population studies, models of age-related diseases, and drug screening for compounds that extend life span are now being investigated using this nematode. 

The building blocks of life involved in ageing seem to the same for all animals. However, for C. elegans, old age and its handicaps come fast – it only lives around 2 weeks. A seven-day old worm has only 5% of the learning capacity of a one-day old worm. In both C. elegans and humans, a metabolite of tryptophan, kynurenic acid (KYNA), accumulates with age. Tryptophan metabolites are known to participate in the regulation of many cells of the immune system and are involved in various immune-mediated diseases and disorders. Kynurenic acid is a product of one branch of the kynurenine pathway of tryptophan metabolism. As it builds up, KYNA interferes with the activity of glutamate, essential in the brain for learning and memory. In humans, it has previously been linked to neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Tuning levels of this chemical in the worm C. elegans, investigators found that could delay and even reverse the declines of old age. In the study published Jan. 31, 2018, in Genes and Development, researchers looked at the effect of KYNA on the ability of this little nematode to learn an association between a neutral smell and food. Researchers found that by keeping KYNA levels low throughout the worm's life, they could prevent the onset of age-related decline – the worms kept learning. In older worms already impaired, lowering KYNA levels could counteract the impairments – raising hope that interventions later in life may be effective in reversing neurological decline.

The reason that KYNA increases with age is still a mystery, but the new study offers an intriguing hint, by linking KYNA build-up in aging worms to elevated levels of insulin, a hormone that controls blood sugar in both worms and humans. In contrast, earlier experiments by the same team had found that fasting, which has been linked to longevity, reduced levels of KYNA in worms and improved learning and memory. Could KYNA be the linchpin through which fasting makes the brain better at learning and aging makes it worse? The influence of KYNA on important neurophysiological and neuropathological processes has been comprehensively documented. In recent years, the link of KYNA to the immune system, inflammation, and cancer has become more apparent. Given this connection, the anti-inflammatory and immunosuppressive functions of KYNA are of particular interest in terms of ageing. Perhaps some link with this interesting metabolite will emerge from the FP7-funded Frailomic study which is looking at reasons why some people become frail earlier than others?


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