How aging better is simply a matter of good science
At Yoxlo we realized that most people age faster than they should. As compared to high performing centenarians, most are experiencing accelerated aging that results in a more than 30-year reduction of their healthspan.
This is our starting point to search for biologically-modifiable mechanisms that are responsible for accelerated aging in common people.
Yoxlo founder Dr. Stef Verlinden is a medical doctor with experience developing medicines for rare genetic diseases and Alzheimer’s. His research prompted two important realizations:
“For most diseases, treatment should start at least a decade earlier than they do today. The discovery of a common pathway for age-related disease could revolutionize how we age.”
For Dr. Verlinden, these revelations sparked a career-switch to developing health products that work to extend our health, before disease sets in. The first is a new product in the making that contains Youngenin, a compound that interferes with the human aging process, so that we can all age like high-performing centenarians. His groundbreaking discovery of the Youngenin compound can work to delay the onset of age-related disease and extend the average healthspan.
But understanding the science behind how Youngenin works begins with a lesson on why we age in the first place.
Why we age
The human body has a natural ability to maintain a balance among its many processes and functions, like heart rate, blood acidity, and body temperature. Scientists call this tremendous ability to maintain and regulate our internal environment homeostasis.
Our bodies also continually replace aged and damaged cells with stem cells, which provide an inexhaustible source of cell rejuvenation and renewal.
“Most scientists agree that biologically, humans should be able to live one hundred years or more in good health, as far as homeostasis and regeneration are concerned.”
But as we age, many things—internal, external, and lifestyle factors—impair the body’s ability to auto-regulate the internal environment and create new cells. Sunlight, free radicals, DNA damage, high impact trauma, too much sitting, stress, overeating, air pollution, alcohol, and smoking are common culprits. DNA damage and a reduced capacity to clean up harmful material inside cells, a process called autophagy, mean that at a certain point, the body can no longer maintain homeostasis like it used to.
As a result, specific proteins become “misfolded” (cannot achieve their normal native state) and aggregate (accumulate and clump together). These protein aggregates are associated with a variety of debilitating diseases.
For example, tau is a neuronal protein whose aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease. Amyloid-beta (Aβ) accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain.
At the same time, the concentration of specific organic molecules becomes so high that they start to crystallize (e.g. from cholesterol, calcium oxalate, or uric acid).
Cell death and disease
Another problem during aging is the gradual build-up of senescent or ‘zombie’ cells. Naturally, cells are programmed to clear themselves when they become too old. Zombie cells are cells that become severely dysfunctional by DNA damage or toxins. As a result, they can not divide any longer, nor can they clear themselves anymore.
The first problem is that since they do not die, senescent cells are not replaced with new stem cell derived cells, thereby disrupting the normal rejuvenation of that tissue or organ. Secondly, zombie cells also secrete IL-1β and other pro-inflammatory cytokines. As such senescent cells contribute to inflammaging. To make things worse, zombie-cells' key feature is that they secrete inflammatory proteins, adding to the inflammaging process.
NLRP3 plays a pivotal role in aging
NLRP3 is a sensor for the immune system that wards off infections and tissue damage. Luckily, it rarely has to come into action. The problem is that NLRP3 is a highly promiscuous inflammasome that is activated by the aggregated proteins and crystals described above.
“Aging and age-related diseases share some basic mechanistic pillars that largely converge on inflammation.”
The result is an almost unnoticeable chronic low-grade inflammation leading to a small but significant increase in the inflammatory cytokines interleukin (IL)-1β in the body. As we know now, this increase plays a pivotal role in the pathology of almost all age-related diseases. Blocking NLRP3 has been tested in the lab, with miraculous results.
“Blocking NLRP3 in mice not only prevents these diseases but also prevents senescence. As a result, these mice showed an extended healthspan, and they lived 30% longer than normal mice.”
As six different NLR sensors partly overlap in their primary function, the defense against pathogens, NLRP3 seems dispensable, which is proven by the long-living mice.
A large placebo-controlled randomized clinical trial proved with level 1 certainty* that lowering IL-1β prevents diseases such as gout, arthritis, cardiovascular disease, and cancer in humans (Ridker et al, 2017). However, blocking IL-1β renders all six NLRs ineffective, thereby increasing the risk of infection. Therefore, blocking NLRP3 specifically is a better approach.
High-performing centenarians (HPC) live in good physical and mental health until the age of one hundred. What is remarkable is that HPCs are not affected by an unhealthy and sedentary lifestyle. Therefore their exceptional healthspan must be explained by one or more genetic advantages.
Of great interest is that HPC’s produce 80% less NLRP3 than ordinary people do and thus, have minimal secretion of IL-1β. It is as if they have won the genetic lottery.
Compared to HPC’s, ordinary people have a more than 30% reduced healthspan. For this reason we choose this innate immune system receptor as our first target to extend the number of years lived in good health. This discovery is the backbone of why healthy adults should take action now.
“Youngenin replicates the phenomenon behind independent, active, high-performing centenarians—so that all of us can stay youthful for longer.”
Mimicking healthy centenarians by inhibiting NLRP3 with Youngenin
The subsequent chronic-low grade inflammation plays a pivotal role in the pathology of age-related diseases, which can be prevented by the knock-out or inhibition of NLRP3.
This is the mystery behind high-performing, disease-free centenarians. These remarkable individuals have a crucial biological mechanism that inhibits the persistent inflammation that leads to age-related disease: low levels of NLRP3 and thus, minimal secretion of IL-1β.
Yoxlo’s first health product contains the compound Youngenin, a proprietary small molecule that lowers IL-1β in human cells. A low level of IL-1β is clinically proven to reduce persistent inflammation and prevent serious diseases associated with old age. This, in turn, increases the human healthspan.
What is a healthspan?
A good life is more than just a long lifespan. Yoxlo’s research promotes prolonging something far more important, a long human healthspan.
Someone past their healthspan means they are chronically sick, often with a degenerating condition.
“A healthspan is the period of one’s life that is healthy, free from serious disease.”
Even the World Health Organization developed a healthy life expectancy indicator (called the HALE) marking the average healthspan by taking the average age of the first occurrence of the most common serious diseases, determining their incidences, and taking the average of those two numbers.
If the average lifespan in the US was 78.79 years in 2019, the HALE for both sexes in the same year is only 66.1 years of age. That leaves the last 12.69 years of the average life faced with the aging and illness we come to associate with growing older.
Yoxlo founder Dr. Stef Verlinden hopes to shrink the years marked by deterioration and lengthen the healthspan by taking a supplement containing Youngenin, so that everyone can enjoy more years of mental and physical health, just like high-performing centenarians. They have reached the age of 100 and are still at their best.
“Knocking out NLRP3 in mice has shown to prolong their life by 30%.”
A dearth of other research shows the pathology of age-related diseases can be prevented by the knock-out (NLRP3-/-) or inhibition of NLRP3, thereby increasing health- and lifespan. The finding that the healthspan of research animals is significantly increased by blocking NLRP3 validates this hypothesis and proves that this is a viable approach to add healthy years to one’s life.
Old NLRP3-/- mice show increased glucose tolerance and increased SIRT1, autophagy, NAD+, and mitochondria levels. They also have decreased IGF-1 and TNF-⍺ levels (Cañadas-Lozano et al., 2020, Marín-Aguilar et al., 2020). Inhibition or knock-out of NLRP3 also prevents bone and muscle loss (Youm et al., 2013), hypertension (Wang et al., 2014), type 2 diabetes (Huang et al., 2018), gout (Goldberg et al., 2017), osteo- and rheumatoid arthritis (Jin et al., 2011, Vande Wall et al., 2014), liver and kidney fibrosis (Wree et al., 2014, Mulay et al., 2013), macular degeneration (Marneros AG., 2013), cancer (Daley et al., 2017, Lee et al., 2019, Theivanthiran et al., 2020, Zitvogel et al., 2012), Alzheimer’s (Heneka MT et al. (2013), and Parkinson’s (Martinez et al., 2017) disease.
Since NLRP3 activation increases during aging, NLRP3 mediates the vast majority of IL-1β production in aged mice. In NLRP3-/- mice, the age-related rise in IL-1β is 80% lower than in old wild-type mice (Youm et al., 2013). NLRP3 inflammasomes, therefore, are the major source of IL-1β production in aged mice.
“Blocking IL-1β with neutralizing antibodies is the first intervention that is clinically proven to extend health in humans.”
By investing in Yoxlo’s research, we can all mimic the low NLRP3 level in long-lived mice and healthy centenarians, which blocks IL-1β, in the hopes of living younger for longer.
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