Autophagy literally means “self-devouring” – something our cells are doing constantly, breaking down damage and toxic waste products – and Japanese cell biologist Yoshinori Ohsumi has just been awarded the Nobel prize in medicine for his work in uncovering the complex mechanisms that underpin this remarkable internal recycling system. So how does autophagy keep us healthy? Why might dysfunctional autophagy contribute to diabetes, dementia, leukaemia and Parkinson’s disease? And will our new understanding lead to any cures?
The process of autophagy involves gathering up cellular junk and waste, sealing it in the cellular equivalent of a bin bag and transporting it to the cellular rubbish bin, called the lysosome, where enzymes break down the contents. “I often call autophagy the recycling van that delivers the rubbish to the recycling centre,” says Professor Katja Simon, of the Kennedy Institute of Rheumatology in Oxford. It plays a key role in health, disease and ageing, she says: “It is very important to degrade toxic waste for the survival of the cell, and a cell without autophagy cannot survive. But it has also been shown that it is important in disease development, such as in Parkinson’s disease, which is characterised by the accumulation of protein aggregates in neuronal cells. Furthermore, autophagy levels fall in the ageing process. The characteristics of old age, such as wrinkles, hearing loss or cancer, are actually due to falling autophagy levels and the accumulation of toxic wastes in the cells.”
Simon’s work is particularly focused on red and white blood cells and disorders such as leukaemia, in which autophagy doesn’t work properly. She is delighted that Ohsumi has been awarded the Nobel prize. “In the 1960s, he used an electron microscope to see structures and no one knew what they were. He discovered the molecules involved in the process.” Ohsumi’s lab mainly works with yeasts, and has uncovered key genes involved in autophagy. The science has come a long way since the 60s and researchers such as Simon can now measure autophagy by tracking the flow of labelled molecules associated with the process.
Mopping up damaged mitochondria – the powerhouses of cells that release energy – seems to be especially important in preventing diabetes and obesity. When this particular form of autophagy, called mitophagy, doesn’t work properly, toxic chemicals build up that cause further mitochondrial damage. This vicious cycle damages cells in the pancreas that produce insulin, and diabetes can set in. A drug that can fix diabetes and obesity by sorting out disordered mitophagy is an attractive idea, but we’re not there yet.
Another key role of autophagy is found in its link in proteins. In the body proteins are folded into 3D shapes. Aberrant proteins that aren’t folded up properly can form large clumps, or protein aggregates, that can be cleared by autophagy. When autophagy fails, the aggregates damage nerve function. This process is thought to contribute to the changes seen in Parkinson’s disease, including tremors, slow and stiff movement, loss of smell and dizziness. The abnormal accumulation of proteins in the brain may be the common thread in different forms of dementia that cause debilitating loss of memory, language, judgment and cognitive and social functioning.
If scientists can stimulate autophagy, they could effectively stave off or even reverse the effects of ageing. As Simon says, it’s not about making people live for ever, but about finding ways to stay healthy as we live out our lives. Studies on mice have found that stimulation of autophagy removes accumulated misfolded proteins, broken mitochondria and damaged DNA in hearts with age-related changes. But translating this lab work into effective treatments for humans is still a way off.
“Autophagy declines during ageing and this has a major impact in our cells, since they accumulate toxic deposits,” says Ioannis Nezis, an associate professor at the University of Warwick. “This is especially harmful for neurons, since neurons do not divide, and the same cell keeps accumulating garbage. If we understand how autophagy is normally induced to selectively recognise and recycle these toxic deposits, we will be able to find compounds that can activate autophagy and keep its levels steady during the course of a lifetime and therefore avoid the accumulation of cellular garbage. These can be chemical drugs, or natural dietary compounds that can be used as supplements.”
So what can we eat to keep us autophaging efficiently? Nezis says lots of natural compounds have been tested in fruit flies, mice and test tubes, but we still don’t know for certain what works in humans and what amounts are needed. Pomegranates, turmeric, red grapes and red wine look hopeful, but Nezis says you may need litres of wine and kilos of grapes to get the required effect. Supplements containing distilled concentrates of the active molecules may prove more palatable.
Simon points out that cells switch on autophagy in response to starvation. Calorie restriction, such as intermittent fasting in the 5:2 diet or during Ramadan, may help us to live long and healthy lives. It is possible that reducing our calorie intake to 70% of what we have been used to eating will boost our autophagy and help to prevent a wide range of disease. Exercise also promotes more autophagy, as experiments that get mice to run on mini treadmills has shown.
Advice to feast on fruit, veg and red wine is hardly new. But thanks to this year’s Nobel prize-winner, our understanding of the science that underpins it is developing all the time. The next step will be drugs, supplements and interventions that could stave off the ravages of ageing and a host of debilitating diseases. We are not there yet, but we are one step closer.
