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Ageing Young

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By Dannon Stigers, Samuel Fraser & Christopher Easton

New evidence suggests that age-related diseases can begin to develop much earlier than we expect, making prevention more important than cure.

It is expected that dementia will be the leading cause of disease burden in Australia by 2016, and that about 3% of the population will suffer from it by 2050. Already 250,000 people in Australia suffer from Alzheimer’s disease. Almost every one of us knows a senior citizen, be it family or friends or neighbours, who tends to be forgetful or has trouble completing daily tasks like dressing or feeding themselves.

We have to ask ourselves why it is primarily the older generations that are affected and whether can we prevent this from happening to us when we start to age. The key component to finding a way to cure or prevent age-related diseases is to understand how they develop.

We set out to study this, and have found a significant new cause of such age-related diseases. The bad news is that these conditions begin to develop much earlier than we previously thought. The good news is that they may be largely preventable if we treat them at this stage, saving the country enormous amounts in health costs. But it’s going to take a completely different health strategy than what we currently have in place.

Free Radicals Damage Proteins
Our bodies are constantly exposed to free radicals produced in both the environment and inside us. These extremely reactive but short-lived molecules can damage all parts of us, from the very small nucleic bases that make up our DNA to the much larger cells that make up organs like the brain and heart. The damage caused by reactions with free radicals leads to diseases like Alzheimer’s or atherosclerosis, which is caused by hardening of the arteries.

Because the older generations have been alive longer, their longer exposure to free radicals is believed to be the root cause of age-related diseases. How that happens biochemically is not certain.

In order to combat free radicals, our bodies produce chemicals called anti-oxidants. However, as we age, our ability to produce these antioxidants diminishes and we become more susceptible to the dangerous effects of free radicals.

A significant portion of age-related diseases stem from the degradation of proteins. These large molecules are responsible for the vast majority of biological processes that happen inside our bodies. They are composed almost exclusively of 20 naturally occurring amino acids that are bound together in a linear fashion. As they form, they fold into distinctive three-dimensional structures that are held together by interactions between two or more amino acids. This folding behaviour is what allows proteins to complete the functions necessary for us to live.

Free radicals can damage these proteins through a process known as oxidative stress, which causes them to fold incorrectly. The amino acids in the protein become chemically modified by the radicals, causing the necessary interactions between them to break down. If proteins do not fold into their required shape they cannot perform their required function, which leads to medical problems.

This has been the long-standing explanation for how oxidative stress makes proteins inactive. However, our research suggests that an alternative pathway needs to be considered. We have been able to determine that damaged amino acids can be used to build proteins inside our cells. This is contrary to what is known about the fidelity of protein synthesis.

An Alternative View
Evolution has developed a method to ensure that proteins are only made from the 20 normal amino acids and not from anything else. While Nature has developed this near-perfect process for protein synthesis, age-related diseases could stem from the mistakes made during this process instead of from oxidative stress on proteins.

So how do our bodies make the proteins that perform their necessary functions so we can be healthy? Humans can produce some amino acids internally but not all of the 20 that make up proteins. We need to ingest the “essential amino acids” that our bodies can’t make by consuming food. Our bodies then use proteins called synthetases to pick up the correct amino acid and help to insert it into the growing protein from the ribosome.

These synthetases have a built-in mechanism to ensure that only the correct amino acid has been picked up, a process called proofreading. It’s this proofreading process that Nature has developed to ensure the fidelity of protein synthesis. It is also this process that can allow damaged amino acids to substitute for normal ones.

So how did we figure this out? In the laboratory we needed to have an experimental set up that allowed us to test lots of differently damaged amino acids and see if they could be incorporated into proteins. In order to model the inside of a living cell, we use cellular extracts from E. coli. We grow large amounts of cells and then break open their membranes to extract the protein-making machinery. This is then added to a test tube where we can control what goes into the extract. We then add the damaged amino acid and determine if it is incorporated into a protein. Surprisingly, we found that several kinds of damaged amino acids cannot be distinguished from the normal 20.

Our results suggest that diseases like Alzheimer’s and atherosclerosis actually begin to develop much earlier than anticipated, and it is not until we reach our 50s, 60s and 70s that they begin to affect our lives in a noticeable way. This means that disease prevention is much more important than a cure.

This idea is radically different than those held by pharmaceutical companies, which have focused their attention on drugs that relieve the symptoms of age-related diseases without eradicating the cause. Instead, we think that the focus should shift towards prevention.

Looking After the Future
Our bodies produce antioxidants to help combat free radicals generated inside us, but that process doesn’t work well forever. In order to keep our bodies safe from this internal damage, we need to consume foods that are rich in antioxidants like apples, strawberries and kidney beans and exercise regularly to keep ourselves as fit as possible as we age into our golden years. By using what we already know about oxidative stress and ageing, we can hope to prevent the onset of diseases that first develop when we are young.

We have published our findings in Chemical Communications in the UK, and are now looking at using Nature’s mistakes to our advantage. We may one day be able to make proteins with new functions that Nature hasn’t developed.

Dannon Stigers is a Postdoctoral Fellow, Samuel Fraser is a PhD student and Christopher Easton is a Professor at the Australian National University’s Research School of Chemistry.