Buck professor Brian Kennedy talks about AKG and the potential for supplements to deliver real anti-aging benefits.
Following Tuesday’s news from the Buck Institute about the compelling new study results for alpha-ketoglutarate (AKG) in mice, the paper’s senior co-author, Buck professor Brian Kennedy, spoke with us about the significance of the results.
Longevity.Technology: A leading figure in the field aging research, Kennedy is also the director of Centre for Healthy Longevity at the National University of Singapore (NUS). Working together with Gordon Lithgow’s lab at the Buck, Kennedy had originally been seeking defined combinations of natural products that had synergistic or additive effects on aging – initially in worms.
“Out of a screen of several dozens of compounds that were already linked to aging, the molecule that jumped out at us was alpha-ketoglutarate,” said Kennedy. “So then we started looking at it in mice.”
Importantly, the AKG was fed to mice at 18 months – late middle age, which is reflective of the age that Kennedy would like to start clinical studies in humans.
“And so what we found is it extends lifespan modestly – about five to 10%, but the big effect is on frailty – it reduces frailty by 50%,” he says. “So I think this molecule is the first one that’s reported to compress morbidity in animal models – the animals stay healthy and then they crash at the end.
“I think a lot of interventions probably extend both healthspan and lifespan similarly, so you still have that period of morbidity. But this one seems to compress it, and we’ve got two rounds of longevity experiments to support that.”
The other key factor for Kennedy is the well-established safety profile of AKG.
“We’re pretty excited because we have a molecule that’s extremely safe,” he says. “There have been clinical trials up to six grams a day with no side effects – bodybuilders have been taking this for a long time. So there’s a lot of human data out there, and it has the potential to really extend healthspan in people.”
The work into AKG is sponsored by Longevity company Ponce De Leon Health, which bases its Rejuvant LifeTabs product on the molecule; Kennedy is also chief scientific officer at the company.
“The company has produced two products, one for men and one for women, that both contain alpha-ketoglutarate,” says Kennedy. “But they also have different vitamins and that’s based on some of the synergistic stuff we were looking at.”
Kennedy is now planning a human clinical trial on people aged 45 to 65 years old at his NUS centre.
“The reason I want to do that is I want to get more into the mechanism for what’s going on,” he says. “So in this paper, we know that several components of the frailty are highly affected like coat condition – prevents the greying of the fur, it prevents alopecia, it had effects on kyphosis and some of the other parameters we looked at. And so there are a lot of measures of healthspan that are affected. What we don’t report in that paper is the mechanism yet.”
Aged-matched control and AKG-fed female mouse (on the left). Animals are 28 months old in the captured picture and the AKG mouse received AKG for 10 months.Kennedy likens supplementing with AKG to similar initiatives using NAD.
“It’s like NAD in the sense that AKG levels are reported to go down with age, and so you’re supplementing levels back up to more of a youthful level,” he says. “The other thing is that it’s involved in thousands of chemical reactions in the body. And so when you’re trying to figure out which are the ones that are relevant to aging, it’s a big challenge.”
Kennedy points out that AKG is a substrate for demethylases, which may be affecting the epigenetic clock, but it’s also involved in central metabolism, linking amino acid catabolism and carbohydrate metabolism, and it may even be giving cells metabolic flexibility.
“We are not publishing this yet, but we know that AKG is increasing glutathione levels in red blood cells, and we think that could be very important,” he says. “If you make more glutathione in red blood cells, you get better oxygen carrying capacity to peripheral tissues, and that’s probably why the muscle function is better. And I think that’s why people take it for muscle endurance.”
While human studies have looked at the effects of alpha-ketoglutarate in a range of different areas, Kennedy is keen to focus exclusively on aging.
“The problem is that most of the human studies don’t look specifically at alpha ketoglutarate, and I’m not a big fan of throwing a bunch of amino acids in for aging,” he says. “When you link AKG to an amino acid, I don’t know what kind of effects you’re going to have on aging.”
While AKG is a natural product and generally regarded as safe, Kennedy is taking no chances with his planned trial at NUS.
“We don’t have to do a safety trial but we want to get that data just to be careful about it,” he says. “Also, it’s a nine month study, so we’re going to use a range of aging biomarkers and inflammatory markers to try to get efficacy data out of it too.”
Despite the delaying effect of COVID-19, Kennedy expects to see human clinical data by early to mid-2021.
“… If we can show reduced inflammation, which is something we clearly see in the mice, and if we can show changes in epigenetic clock, which we think we’re going to be able to, then that’ll be better than any molecule that’s out there… ”
With the market for anti-aging supplements growing quickly, Kennedy is broadly positive that the supplementing approach has good potential for success.
“The supplement industry in the aging space is evolving and a lot of scientists that are aging experts are actually getting in now and starting to test these things,” he says. “I honestly couldn’t tell you which ones work and which ones don’t because most of them haven’t been tested well, but I do think there’s great promise in them.”
“It’s still a problem to get drugs approved for aging, and I hope that gets solved. But in the meantime, I think the first set of really effective interventions may be supplements that get tested adequately, validated and then use put it into widespread use, and so I’m very excited about this space.”
“Maybe futuristic stem cell stuff is the is the ultimate end point here but, for the time being, if we can get a modest extension of healthspan, the economic and quality of life benefits of that are huge.”
