Could NAD+ supplements be the answer to maintaining youthful energy and preventing age-related diseases? Photo / 123rf
Can NAD+, the latest longevity pill, help us restore our youthful vigour and avoid age-related disease?
On noticing her energy levels dropping in the lead-up to turning 60, Kim Arculli Walker turned to a longevity supplement, after listening to a talk given by the Harvard professor David Sinclair.
Sinclair, something of a celebrity within the longevity field, had waxed lyrical about the wonders of NAD+, pointing out that its levels wane within the body with age.
Until relatively recently, no one apart from the most ardent longevity scientists had heard of NAD+, or nicotinamide adenine dinucleotide, to provide its full name.
But over the last two years, peptides like NAD+, small chains of amino acids that can help activate vital cellular functions in the body, are increasingly being touted as a way to reverse some aspects of ageing.
NAD’s main use is to convert the energy within the food we eat into a form which can be utilised by the body. “It’s a bit like a battery,” says Mathias Ziegler, a professor at the University of Bergen in Norway who runs a lab funded by the Norwegian Research Council studying NAD+. “It’s charged and then discharged.”
Increasing NAD+, the uncharged form of the molecule, helps to boost energy levels throughout the body and encourages our cells to repair themselves, a process which happens less and less efficiently as we get older, which contributes to many of the signs of ageing.
The reason why NAD+ has attracted the interest of longevity scientists is that it plays a key role in more than 400 different enzyme reactions in the body, the intrinsic chemical processes which make our cells tick and keep us alive. It exists in two states, NADH and NAD+, and over the past 15 years numerous experiments have shown that increased levels of NAD+ can extend lifespan – albeit in mice and worms so far, rather than humans.
That hasn’t prevented influencers, mostly in the United States, from using it. Biohackers such as the billionaire Bryan Johnson and celebrities such as Hailey Bieber, best known as wife to Justin Bieber, and Kendall Jenner, have been reportedly receiving NAD+ via IV infusions, or precursor supplements which can include NMN but also other molecules such as nicotinamide riboside (NR).
While many of the celebrities reportedly receiving NAD+ infusions are still in their 20s, Prof Ziegler says that its levels do not start to noticeably decline until at least the age of 35. However, past a certain age NAD+ clearly plummets. Some research indicates that by middle age, NAD+ levels have halved compared to our 20s.
This has biological consequences, and some research has suggested that this contributes to diminished insulin sensitivity, leading to the onset of metabolic syndrome which raises the risk of developing diabetes, heart disease, stroke, or all three, as well as problems with mitochondria, the body’s power plants which fuel our cells and organs.
Animal experts have suggested that boosting NAD+ can reverse mitochondrial dysfunction – when the body’s cell batteries effectively shut up shop resulting in extreme fatigue – and improve insulin sensitivity. Other studies in human cells and rodents have also indicated that this may improve the heart’s pumping capabilities and reduce inflammation, although the evidence remains mixed.
Prof Ziegler is encouraged by some small studies of age-related diseases in humans. Last week the journal Nature Communications published a study which gave NR supplements to 90 people with peripheral artery disease, a condition which prevents the delivery of oxygen and nutrients to skeletal muscle in the extremities, causing severe walking disability.
After six months of supplementation, the majority of participants, who were mostly in their 70s, showed improvement. “There’s a test called the six-minute walk,” says Prof Ziegler. “These people can’t walk very well because the blood circulation in the legs is very bad. But they improved in the study which was encouraging.”
However, when it comes to healthier, middle-aged adults, there are still many questions which need to be addressed before we start prescribing NAD+ boosters.
Prof Joseph Baur of the University of Pennsylvania’s Perelman School of Medicine is an expert in the mechanisms of ageing, who has been exploring the role of NAD in ageing.
Prof Baur says that if you are going to take NAD+, there is more evidence for taking NAD+ precursor supplements rather than infusions.
“There is a lot more safety data available for oral supplements at present,” he says.
“While I would expect both to be safe, I think we still really need to document that for the IV route.”
However, not everyone is convinced by the evidence available so far.
Dr Federica Amati, the head nutritionist at Zoe, points out that there is a lack of data demonstrating that supplementation is safe.
“Just because you’re missing something that’s created by your own cells, adding it to your body doesn’t come without side effects,” she says.
“One problem is that when you add NAD+, it speeds up other processes. So in one mouse model, it accelerated rates of pancreatic cancer. People are handing it out left, right and centre, but there haven’t been safety trials.”
Prof Ziegler also notes that many of the studies which have shown benefits in animals have used extremely large doses of NAD+. The problem with replicating this in humans is that we don’t know whether it would prove toxic over the long term.
He predicts that boosting NAD+ over the course of a few days or weeks will likely pose little danger, but the consequences of doing so for years or even decades remain unknown. Both Baur and Prof Ziegler point to certain problematic metabolites called pyridones which are produced in the body after taking NAD+ enhancing supplements.
“It appears that with higher doses of NAD+, you get more beneficial effects,” says Prof Ziegler.
“They’ve trialled three grams of it per day which was considered safe over four weeks. But if you continue doing that over a long period of time, there are these pyridones which we know exist and are considered dangerous if you accumulate them in some way.
“There is no evidence yet that this happens, but we need to look into that more.”
The other question is whether people might develop a form of tolerance, impairing their own natural ability to produce NAD+ on their own.
“You always have the risk that the body gets too used to it and will need more over time,” says Prof Ziegler. “And if you then stop the supplements, will the body be ready to do it itself again?
Another issue is that while supplements or infusions boost NAD+ levels in the blood, there is relatively little evidence that they actually increase NAD+ in different tissues around the body where it is most needed.
“There is no readily accessible method to measure NAD levels in the tissues where it likely plays more critical roles,” says Prof Baur.
“This is presently done only in limited numbers of subjects through biopsies or costly and time-consuming magnetic resonance studies, for which even most universities lack proper equipment.”
Of course not everyone who takes the supplement is hoping to add decades to their lifespan.
For Arculli Walker, the goal was to regain some of her youthful vigour.
“I just wanted to try something to see if it made me feel younger,” she says.
“I wanted more energy, that was the main thing.”
Living in Hong Kong, she had been aware of NAD+ for almost 10 years after a local business tycoon invested in and brought a NAD+ boosting supplement Tru Niagen to the region.
“He was apparently taking it, and he just never seemed to age,” she remembers.
Her interest was further piqued by stories from friends who had tried various NAD+ precursors, supplements which are absorbed and converted into NAD+ within the body’s cells. One had tried a particular precursor known as NMN (nicotinamide mononucleotide) and even had to stop because she found her hair was thickening so much.
Arculli Walker says that she too began experiencing benefits. Within days, she started feeling notably stronger.
“For the first month, I really noticed it,” she says. “Everything just felt better. I could walk a hill, my heart rate was calmer.”
Over the last few months Arculli Walker has experimented with various combinations of NAD+ precursors. However, she is still making up her mind whether it is a fad or the real deal.
“The effects have worn off a little, so I’m not so sure how much of a difference it’s making,” she says. “Apparently they’re now making these supplements for pets so I might give them to my dogs to see if there’s any difference. That way I’ll know it’s not my mind playing games with me.”
While NAD+ has been dubbed a “longevity molecule” in the popular media, the people who stand to benefit most from this research in the shorter term are rare disease patients.
According to Prof Ziegler, people with diseases related to mitochondrial dysfunction may benefit as well as patients experiencing degeneration of the central nervous system.
Last year, early results from a clinical trial in Norway, which saw 13 patients with ataxia receive 18 months of NR supplementation, found that they saw notable improvements in motor coordination and eye movement control.
People with ataxia usually suffer from poor balance, difficulties with fine motor control such as writing or eating, unsteady walking, issues swallowing and persistent back and forth eye movement.
While there are some intriguing signs that it may help tackle some of the hallmarks of ageing, scientists studying NAD+ feel that we don’t know enough to be marketing it to healthy individuals.
“I don’t think we have the evidence yet to be confident that NAD+ supplements will improve long-term health or extend lifespan,” says Prof Baur.
“I think any supplement has risks and they should always be viewed in terms of a risk/benefit analysis.”
Given the extent of the hype surrounding NAD+, Prof Baur would like to see a much larger clinical trial aimed at assessing whether it demonstrates benefits in healthy older adults, along the lines of the Tame trial in the United States for metformin, another supplement linked to longevity.
“I would love to see a larger prospective study and this is certainly a possibility for NAD supplements,” says Prof Baur.
Of course, there is always the question of whether it is really ethical to extend human lifespan, with the global human population surpassing eight billion towards the end of 2022.
Prof Ziegler, who is 62, says it is unlikely that boosting NAD+ or any of the other current longevity supplements will suddenly help us live to 150.
Instead, he feels that the main goal is trying to improve healthspan and reduce the burden on the world’s healthcare systems by enabling people to avoid age-related diseases for longer.
“I’m fascinated by science and technology and so I’d love to see what we have in 200 years time,” he says.
“Have we managed to make it to Mars? But realistically in my view, 20 more years of good health would be a lot of fun. I think this is the important goal, can we help more people live to their eighties and beyond without developing a chronic illness.”
Baur recommends that anyone interested in increasing their NAD+ levels should look to do so with lifestyle tweaks.
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