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17th October 2014
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Turning back time

Jasmin Fox-Skelly, 17 October 2014

Mitochondrion

The mitochondrial theory of ageing has been around since the 1950s. Simply put, it states that when we are young all our cells have bountiful numbers of healthy mitochondria that make lots of energy in the form of ATP. Over time and into middle age, however, we start to lose our mitochondrial function and one of the main causes of age-related diseases is thought to be this decline in the cell’s ability to make energy.

Back in the 1950s, scientists noticed that as we age the DNA in mitochondria became increasingly degraded, due or so they believed, to the release of harmful free radicals produced as a byproduct of energy production. However, simply feeding animals with antioxidants that soak up free radicals does not extend life, suggesting things are not that simple.

In the past couple of years, a new theory has emerged, which has given scientists hope of finally finding a drug to reverse aspects of ageing. The theory is that mitochondrial function declines not because of free radical damage, but instead from a breakdown in communication between the mitochondria and the nucleus.1 When we are young, certain so-called NAD proteins made in the nucleus of cells travel across the cytoplasm into the mitochondria, where they help them to make the right amount of energy to match the cell’s needs. However, when we reach middle age the nucleus stops making as much of these proteins, bringing about a crisis of communication. If we could restore that communication, we might have a chance of reversing aspects of ageing.

‘The mitochondria and nucleus genomes are like a married couple,’ says David Sinclair, a molecular biologist at Harvard Medical School in Boston, US. ‘What happens is they stop talking over time. We are testing what happens if we can get them talking again.’

In a study in 2013, Sinclair and his team tracked the problem down to a loss of a co-enzyme called nicotinamide adenine dinucleotide (NAD). By simply raising the levels of NAD back to what they would be with a young mouse, the researchers were able to re-establish communication between the nucleus and mitochondria.

One week of NAD boosting youth-medication in two-year-old mice meant their muscles became like those of a six-month-old in terms of mitochondrial function, muscle wastage, inflammation and insulin resistance. This is the equivalent of transforming a 60-year-old human’s muscle to that of a 20-year-old.

Trials on humans are expected to commence as soon as 2015, however, the researchers emphasise that a ‘magic pill’ that reverses ageing is several years away, partly due to the cost of the compound, which would be about $50,000 a day for a human (http://www.theguardian.com/science/2013/dec/20/anti-ageing-human-trials). Rather than making people live until they are 200, the goal of the research is to help people be healthy longer into old age by preventing or delaying the onset of cancer, dementia and diabetes.

‘Currently in medicine, we address these diseases separately, one at a time,’ says Sinclair. ‘What we are trying to understand is: what is the root cause of this decline that we all experience? If we can get to the heart of that then it may open up whole new treatment options that will allow us to treat or prevent many diseases at the same time.’

NAD is not the only compound that could be used to ‘treat’ ageing. Sinclair and his team have a number of other molecules that are currently in human clinical trials.2 All of them work by targeting a single anti-ageing enzyme in the body, SIRT1. This enzyme is switched on naturally when we exercise and when we restrict our calorie intake, but can be ‘enhanced’ by compounds such as resveratrol found in small quantities in red wine. Sinclair and his lab have developed 4000 synthetic activators of the enzyme, which are 100 times as powerful as a single glass of red wine – the most promising three are in human trials.

Rather than spending lots of money designing new drugs, there is also the possibility that existing ones could be ‘repurposed’ to slow the ageing process.  A drug called rapamycin, used to treat cancer and to suppress the immune systems of organ transplant patients, is one of the most promising candidates. Mice given the drug at the relatively old age of 600 days, roughly equivalent to 60 years of age in a person, live up to 14% longer than other rodents,3 and just a short treatment of rapamycin in elderly mice can delay age-related declines in the heart, liver and adrenal glands; reverse many age-related pathologies; and improve function in several organ systems. There are currently clinical trials ongoing for rapamycin in otherwise healthy elderly individuals.

‘Rapamycin definitely works in mice and probably works in people,’ says Matt Kaeberlein, a biochemist at the University of Washington in Seattle, US, who studies ageing, and has no link with any company developing anti-ageing drugs. ‘Unlike other potential drug candidates, rapamycin has already been shown to robustly extend lifespan and promote health span in normally ageing mice. Although [it] does have side effects at higher doses used clinically to prevent organ transplant rejection, the human clinical trials for ageing seem to suggest they aren’t so much of a problem at lower doses. In my opinion, rapamycin is by far the best candidate for a drug to promote healthy ageing in people right now.’

Other drugs that could be repurposed to treat age include painkillers. In a study in 2014,Andrew Dillin, a molecular biologist at the University of California (UC), Berkeley, US, found that mice bred to feel less pain lived longer.4 The mice, which lacked a pain receptor called TRPV1, were less likely to develop diseases such as diabetes in old age. When they got old, they also kept their fast, youthful metabolisms, were able to clear sugar quickly from the blood, and burned more calories during exercise than regular elderly mice.

The slowing of the ageing process in these mice is likely to do with the TRPV1 receptor’s role in regulating insulin, a hormone that promotes the removal of sugar from the blood. TRPV1 neurons in the pancreas stimulate the release of a substance called CGRP, which prevents insulin release. This means that mice bred without the TRPV1 gene had low levels of CGRP and more insulin, explaining their improved glucose tolerance.

The TRPV1 receptor is already a popular target for drug companies trying to treat pain. Many antagonists of the receptor have reached Phase 2 clinical trials, but have been hampered by adverse effects on body temperature, resulting in hyperthermia. Nevertheless, pharmaceutical companies have not given up and several drugs are in trials. Is it possible that these drugs could also be used to mask the signs of ageing?

‘We think that blocking this pain receptor and pathway could be very useful, not only for relieving pain, but for improving lifespan and metabolic health, and in particular for treating diabetes and obesity in humans,’ said Dillin.

There are many drugs that are already trying to target the TRPV1 receptor to treat pain, and drugs that inhibit CGRP function are already in development to treat migraines. These drugs might also be useful for treating diabetes and obesity.’

Alternatively, metformin, the world’s most widely used anti-diabetic drug, could also be used to slow ageing and increase lifespan. In June 2014, Wouter De Haes, a Belgian doctoral researcher, studied the effects of metformin on the tiny roundworm Caenorhabditis elegans, an ideal species for studying ageing because it has a lifespan of only three weeks.5 Normally when they age, the worms get smaller, wrinkle up and become less mobile; however, De Haes found that worms treated with metformin showed very limited size loss and no wrinkling. They not only aged slower, but they also stayed healthier for longer.

De Haes believes that metmorfin has this age defying affect because it increases the number of toxic oxygen molecules released by the mitochondria. Produced as a byproduct when providing the body’s cells with energy, whilst these free radicals can damage proteins and DNA, and disrupt normal cell functioning, a small dose can actually do the cell good, increasing robustness and longevity in the long term, according to the researchers.

‘We discovered that the lifespan-extending effect of metformin on the roundworm was dependent on the increased production of reactive oxygen species,’ says De Haes. ‘Antioxidants, compounds that remove these reactive oxygen species, abolished the lifespan-extending effect of metformin, adding to the growing body of evidence that antioxidants are not as beneficial for health as generally assumed,’ he added.

With so many possibilities for drugs to treat ageing, how long will we have to wait until they are available on the market? ‘I do think drugs that promote healthy ageing are close – more a matter of “when” than “if” at this point,’ says Matt Kaeberlein, associate professor of pathology at the University of Washington, US.

‘Rapamycin is a great contender, and the NAD precursors developed by Sinclair’s lab have potential, although nicotinamide mononucleotide – one of the drugs that boosts NAD – is not a realistic therapeutic option at this point as it is not orally bioavailable. Of course, the only intervention really shown to promote healthy aging in people so far is exercise!’

References

1 Gomes, A. P. et al, Cell, doi: dx.doi.org/10.1016/j.cell.2013.11.037
2 Hubbard, B. P. et al, Science, 2013, 339, 1216
3 Harrison, D. E. et al, Nature, 2009, 460, 392
4 Riera, C. E. et al,  Cell, 2014, 157, (5), 1023
5 De Haes, W. et al, PNAS, 2014, doi: 10.1073/pnas.1321776111

Jasmin Fox-Skelly is a freelance writer based in Cardiff, UK

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