This is how you silence an aging gene

Scientists are on the trail of a gene that speeds up the aging process: when it is taken away from mice, they stay healthier and live longer. In healthy centenarians, it is less active than in normal elderly people. Stef Verlinden, a physician and researcher from Leiden, developed a dietary supplement to suppress this ‘aging gene’. Does he have a powerful anti aging remedy on his hands?

Don’t smoke, drink alcohol in moderation or preferably not at all, eat healthy food, exercise a lot, get enough sleep and don’t stress too much: those who obediently follow these well-known rules of life significantly increase their chances of reaching a respectable age without ailments. That is to say, the average Western European person should be very grateful if, with a healthy lifestyle, he or she may reach eighty and not too rickety. But strangely, this condition does not apply to a rare human species, the high-performing centenarians. These are tough old people who – sometimes smoking, drinking and snacking – live to be a hundred or even older, and in the process are hardly plagued by age-related ailments such as diabetes, arteriosclerosis and cancer. The most famous example is Jeanne Calment, the French woman who holds the world aging record and breathed her last at 122 in 1997. She was still cycling at 100 and lived independently until she was 109. And she loved port, ate a kilo of chocolate a week and smoked until she was 117.

‘What is striking is that these people generally do not have a healthier lifestyle than others at all,’ says Leiden physician and researcher Stef Verlinden. ‘In terms of smoking, drinking, eating and exercising they do not distinguish themselves from ordinary elderly people. American researcher Nir Barzilai is doing research on this group. In that context, he once visited a lady of 103 in New York. That woman opened the door while smoking a cigarette.  Barzilai almost fell over with amazement: Didn’t anyone tell you to stop smoking? Yes, she said, all my four family doctors did, but they are all dead.’

Verlinden has a remarkable vision of the super elderly: ‘These people prove that it is possible to live to at least one hundred years in good health. Instead of seeing them as rare exceptions, we can take them as a measure of normal aging. If you look at it this way, almost all of us are suffering from accelerated aging. The fact that the children of vital centenarians often reach old age even without health problems suggests that hereditary traits are at play. As researchers, let’s focus on those traits. Can we influence them preventively? Can we mimic the genetic advantage of healthy centenarians so that we can all reach a healthy 100?’

Verlinden thinks this is possible. Indeed, he argues that only one gene, NLRP3, probably needs to be addressed to do so. He points to a 2013 study in which this gene was deleted in mice: compared to unmanipulated conspecifics, the animals suffered less muscle and bone loss as they aged, maintained better defenses and stayed mentaly sharp. ‘And guess what, they lived 30 percent longer!’

Genes are pieces of DNA that can code for making a protein. The NLRP3 gene codes for the NLRP3 protein. ‘That protein seems to be a kind of sensor for the innate immune system,’ Verlinden explains. ‘There are a number of these sensors in every cell. The original idea is that these sensors are triggered by a bacterium, virus or by substances that arise from tissue damage.’ Once NLRP3 is activated, a complex chain reaction starts in the cell where a series of pro-inflammatory signaling molecules are formed. The result is that the cell blows itself up, so to speak, in a process called pyroptosis. “With that, the dangerous invader is then immediately cleared away.

Verlinden emphasizes that this self-destruct system is tightly regulated because it has the potential to do a lot of harm. “Otherwise we would probably all be in a lot of pain and not live long. What happens when the NLRP3 system derails is evident in the rare hereditary inflammatory disease cryopyrin associated periodic syndrome (CAPS): Patients suffer violent fever attacks and endure horrific pains.

NLRP3 also plays a role in gout. ‘In this, urea crystals precipitate in the joints,’ says Verlinden. ‘But those ureaum crystals also trigger NLRP3 and then you get rheumatic attacks.’

And that’s an essential new insight: NLRP3 is activated not only by unwanted invaders and substances released from tissue damage, but also by compounds that the aging body itself increasingly produces: cholesterol crystals, the ‘alzheimer’s proteins’ amyloid and tau, and the ‘parkinsonian protein’ alpha-synuclein have all been found to trigger NLRP3 [source, source, source, source]. Moreover, as we age, the mitochondria, the energy factories in our cells, start to function worse. In the process, they secrete more and more pro-inflammatory signaling molecules and harmful oxidants – these too can activate NLRP3 [source].

None of this is enough to cause cells to self-inflate, but rather to excite NLRP3 with advancing age to the point where the body enters a permanent state of inflammation – you don’t feel a thing but in the meantime your health is compromised. This dormant inflammatory activity, also called “chronic silent inflammation” or “inflamm-aging,” is seen as a key component of a range of aging diseases such as dementia, diabetes and cardiovascular disease – and of the aging process itself.

Back to the super elderly, the exceptions who – sometimes despite bad habits – make it to 100 and stay healthy in the process. While NLRP3 activity normally increases steadily with aging, that does not happen in these lucky individuals. They have levels of NLRP3 proteins in their cells at age 100 that are as low as those of younger individuals (29-39 years old) [source]. In addition, they have low levels of a range of pro-inflammatory molecules.

While the role of the NLRP3 gene was revealed in several steps beginning in 2000, scientific attention to it has been rapidly increasing recently. The gene is now associated with type-2 diabetes, cystic fibrosis (cystic fibrosis), myocardial infarction, Alzheimer’s, parkinson’s and various cancers, among others. In the fight against these calamities, several research groups and pharmacists are experimenting with drugs that inhibit NLRP3 [source]. In fact, several drugs that counteract NLRP3 itself or NLRP3-related inflammatory compounds are already being used in some diseases. However, the problem with the existing NLRP3 inhibitors is that they work weakly and/or cause side effects.

Verlinden decided to hunt for a substance that dampens NLRP3 effectively and without side effects. Suppose that you could safely keep NLRP3 in check…Verlinden suspects that by doing so, you could imitate an important genetic trait of healthy centenarians, allowing you, as a mere mortal, to simply add ten or twenty healthy years. His thought is that with the help of a drug that inhibits NLRP3, we can switch back to a slower aging rate and become as indestructible as the vital centenarians.

Verlinden delved into the scientific literature on NLRP3 inhibitors and came across a promising compound from Indian redwood. He christened it Youngenin, started the biotech start-up Yoxlo (‘Yoxlo believes you can be as active at 95 as you are today, by slowing the age process now’) and went looking for investors. The latter is no small task. ‘It is extremely expensive and time-consuming to bring a new drug to market, and there is a real chance that it will fail because it does not meet expectations or has too many side effects,’ he says. ‘Potential investors always want to know two things from me: Do you use it yourself and is there a market for it? To both questions I have to answer in the negative. Because Youngenin’s safety has yet to be demonstrated, and I didn’t have a marketable anti-aging product in hand with which to show that there is a demand for it.’

While Verlinden wrestled with the hurdles involved in drug development, a remarkable scientific publication caught his eye. In it, Rajogopa Sekhar, an American researcher of Indian descent, described how elderly subjects had improved cognitively by taking two amino acids that have long been on the shelves of vitamin stores: glycine and N-actelylcysteine (NAC). ‘I have to be honest that at first I thought: these amazing effects with two amino acids, that can’t be true, can it? But I woke up when I started looking further and found out what these amino acids do in our bodies.’

As described above, as we age, the mitochondria, the power plants of our cells, produce energy less and less efficiently while emitting more and more oxidants. These oxidants damage cells and are considered a major cause of disease and aging. Cells protect themselves from oxidants by making a very powerful antioxidant: glutathione. However, with age, the production of this valuable substance declines significantly [source, source]. Why is that? Glutathione consists of three amino acids: glutamic acid, glycine and cysteine. You get these with food and the body can also make its own. Sekhar had discovered that the availability of glycine and cysteine in cells nevertheless decreases in the elderly. And therefore the production of glutathione stagnates. With a series of experiments, Sekhar demonstrated that you can completely and safely restore the level of glutathione by taking additional glycine and cysteine (in the form of NAC) [source]. Sekhar calls the combination GlyNac. Older subjects not only regain their youthful glutathione levels thanks to GlyNac, they become more like young people in numerous other ways. In older subjects, taking GlyNac leads to, among other things:

-Diminished chronic inflammatory processes

-Improved endothelial function (healthier blood vessels)

-Improved blood sugar management (59 percent less insulin resistance on average)

-Lower breakdown of muscle protein (less sarcopenia)

-Lower fat percentage and abdominal girth (slimmer!)

-Improved scores on all measured cognitive functions (smarter and sharper)

-Improved walking speed and pinch strength (faster and stronger)

-Improved function of mitochondria

Whether subjects will also live longer thanks to GlyNac is impossible to say based on Sekhar’s experiments. However, mice he fed GlyNac lived 24 percent longer [source], almost as long as mice in which the NLRP3 gene was deleted.

According to Sekhar, the broad rejuvenating effects of glutathione are due to its powerful antioxidant activity. Verlinden, however, has an important additional explanation: “Glutathione is also an NLRP3 inhibitor! He points to a scientific review article from 2022. This describes how, according to recent findings, declining glutathione levels are associated with a wide range of ailments, from mental deterioration to autoimmune diseases, all of which are characterized by erroneous activation of NLRP3. According to the authors, therefore, glutathione plays a central role in influencing NLRP3: the lower the glutathione level, the more active NLRP3 is. If glutathione levels remain high, NLRP3 also does not stir.

Glutathione attenuates NLRP3 not only directly, but also in a roundabout way thanks to its beneficial effect on mitochondria. As also seen in Sekhar’s experiments, increasing glutathione with GlyNac causes rusty mitochondria to perform better again. As a result, they emit fewer alarm substances and oxidants that excite NLRP3.

While scientists and pharmacists are diligently searching for medicinal NLRP3 inhibitors, the authors conclude their review article by suggesting the use of glutathione in NLRP3-related diseases: unlike pharmaceutical compounds that often cause side effects, glutathione belongs naturally in the body and its administration has long been known to be safe. However, Sekhar argues in this blog that it is more beneficial and better to let the body produce more glutathione itself by taking GlyNac.

Verlinden decided to temporarily abandon Youngenin’s trail and make his own dietary supplement with GlyNac. ‘After all, with this I can do two things: I can use it myself and I can show that other people want it too, in short that there is a potential market for this kind of anti-aging product. With that, I may then be able to interest investors to continue with the rest of the research on Youngenin.’

Putting together a supplement with GlyNac turned out not to be as easy as he had initially thought. ‘There are two problems with GlyNac as a dietary supplement: you need a high dose of it and most people find NAC very gross. It tastes like rotten eggs and is very sour. But if you put a daily dose of GlyNac in capsules that you can easily swallow, you have to take handfuls of it. That’s why I developed a drinking powder with additional substances that still make it taste good. With the daily dose, you get the amount of GlyNac that Sekhar uses successfully in his subjects.’

The GlyNac powder has been available for almost a year, and Verlinden has turned his attention back to Youngenin. Because the physician-researcher sees opportunities to combine his findings with Youngenin and GlyNAC to come up with a new formulation that can inhibit NLRP3 even more potently than the compounds individually. Meanwhile, he mimics the genetic advantage of vital centenarians by faithfully drinking his own smoothie with GlyNac every day.

Text Pim Christiaans / Life Unlimited

P.S. Rajogopa Sekhar used glycine and N-acetylcysteine in high doses for his research. At a body weight of 75 kg, these amounted to 7.7 grams of glycine and nearly 10 grams of NAC.