From COSMOS: “Can ageing be held at bay by injections and pills?”
24 March 2017
Two fast ageing mice. The one on the left was treated with a FOXO4 peptide, which targets senescent cells and leads to hair regrowth in 10 days.
Peter L.J. de Keizer
The day we pop up a pill or get a jab to stave off ageing is closer, thanks to two high profile papers just published today.
A Science paper from a team, led by David Sinclair from Harvard Medical School and the University of NSW, shows how popping a pill that raises the levels of a natural molecule called nicotinamide adenine dinucleotide (NAD+) staves off the DNA damage that leads to aging.
The other paper, published in Cell, led by Peter de Keizer’s group at Erasmus University in the Netherlands, shows how a short course of injections to kill off defunct “senescent cells” reversed kidney damage, hair loss and muscle weakness in aged mice.
Taken together, the two reports give a glimpse of how future medications might work together to forestall ageing when we are young, and delete damaged cells as we grow old. “This is what we in the field are planning”, says Sinclair.
Sinclair has been searching for factors that might slow the clock of ageing for decades. His group stumbled upon the remarkable effects of NAD+ in the course of studying powerful anti-ageing molecules known as sirtuins, a family of seven proteins that mastermind a suite of anti-ageing mechanisms, including protecting DNA and proteins.
Resveratrol, a compound found in red wine, stimulates their activity. But back in 2000, Sinclair’s then boss Lenny Guarente at MIT discovered a far more powerful activator of sirtuins – NAD+. It was a big surprise.
“It would have to be the most boring molecule in the world”, notes Sinclair.
It was regarded as so common and boring that no-one thought it could play a role in something as profound as tweaking the ageing clock. But Sinclair found that NAD+ levels decline with age.
“By the time you’re 50, the levels are halved,” he notes.
And in 2013, his group showed [Cell] that raising NAD+ levels in old mice restored the performance of their cellular power plants, mitochondria.
One of the key findings of the Science paper is identifying the mechanism by which NAD+ improves the ability to repair DNA. It acts like a basketball defence, staying on the back of a troublesome protein called DBC1 to keep it away from the key player PARP1– a protein that repairs DNA.
When NAD+ levels fall, DBC1 tackles PARP1. End result: DNA damage goes unrepaired and the cell ‘ages’.
“We ‘ve discovered the reason why DNA repair declines as we get older. After 100 years that’s exciting,” says Sinclair .
His group has helped developed a compound, nicotinamide mono nucleotide (NMN), that raises NAD+ levels. As reported in the Science paper, when injected into aged mice it restored the ability of their liver cells to repair DNA damage. In young mice that had been exposed to DNA-damaging radiation, it also boosted their ability to repair it. The effects were seen within a week of the injection.
These kinds of results have impressed NASA. The organisation is looking for methods to protect its astronauts from radiation damage during their one-year trip to Mars. Last December it hosted a competition for the best method of preventing that damage. Out of 300 entries, Sinclair’s group won.
As well as astronauts, children who have undergone radiation therapy for cancer might also benefit from this treatment. According to Sinclair, clinical trials for NMN should begin in six months. While many claims have been made for NAD+ to date, and compounds are being sold to raise its levels, this will be the first clinical trial, says Sinclair.
By boosting rates of DNA repair, Sinclair’s drug holds the hope of slowing down the ageing process itself. The work from de Keizer’s lab, however, offers the hope of reversing age-related damage.
His approach stems from exploring the role of senescent cells. Until 2001, these cells were not really on the radar of researchers who study ageing. They were considered part of a protective mechanism that mothballs damaged cells, preventing them from ever multiplying into cancer cells.
The classic example of senescent cells is a mole. These pigmented skin cells have incurred DNA damage, usually triggering dangerous cancer-causing genes. To keep them out of action, the cells are shut down.
If humans lived only the 50-year lifespan they were designed for, there’d be no problem. But because we exceed our use-by date, senescent cells end up doing harm.
As Judith Campisi at the Buck Institute, California, showed in 2001, they secrete inflammatory factors that appear to age the tissues around them.
But cells have another option. They can self-destruct in a process dubbed apoptosis. It’s quick and clean, and there are no nasty compounds to deal with.
So what relegates some cells to one fate over another? That’s the question Peter de Keizer set out to solve when he did a post-doc in Campisi’s lab back in 2009.
Finding the answer didn’t take all that long. A crucial protein called p53 was known to give the order for the coup de grace. But sometimes it showed clemency, relegating the cell to senesce instead.
De Keizer used sensitive new techniques to identify that in senescent cells, it was a protein called FOXO4 that tackled p53, preventing it from giving the execution order.
The solution was to interfere with this liaison. But it’s not easy to wedge proteins apart; not something that small diffusible molecules – the kind that make great drugs – can do.
De Keizer, who admits to “being stubborn” was undaunted. He began developing a protein fragment that might act as a wedge. It resembled part of the normal FOXO4 protein, but instead of being built from normal L- amino acids it was built from D-amino acids. It proved to be a very powerful wedge.
Meanwhile other researchers were beginning to show that executing senescent cells was indeed a powerful anti-ageing strategy. For instance, a group from the Mayo Clinic last year showed that mice genetically engineered to destroy 50-70% of their senescent cells in response to a drug experienced a greater “health span”.
Compared to their peers they were more lively and showed less damage to their kidney and heart muscle. Their average lifespan was also boosted by 20%.
But humans are not likely to undergo mass genetic engineering. To achieve similar benefits requires a drug that works on its own. Now de Keizer’s peptide looks like it could be the answer.
As the paper in Cell shows, in aged mice, three injections of the peptide per week had dramatic effects. After three weeks, the aged balding mice regrew hair and showed improvements to kidney function. And while untreated aged mice could be left to flop onto the lab bench while the technician went for coffee, treated mice would scurry away.
“It’s remarkable. it’s the best result I’ve seen in age reversal,” says Sinclair of his erstwhile competitor’s paper.
Dollops of scepticism are healthy when it comes to claims of a fountain of youth – even de Keizer admits his work “sounds too good to be true”. Nevertheless some wary experts are impressed.
“It raises my optimism that in our lifetime we will see treatments that can ameliorate multiple age-related diseases”, says Campisi.
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