Microbiome, Aging, and the Synthetic Immune System: A New Frontier in Geroscience

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Now, let’s get to this week’s topic!

What does aging have in common with pathogens like bacteria and viruses? And how does the quest to tackle antimicrobial drug resistance -- an alarmingly growing healthcare crisis in its own right -- may also be a potential game changer for aging research?

To start understanding this relation, we should zoom out a bit and recall the role of microorganisms (mostly bacteria) in our own body functioning and health. When I first read it years ago, it was pretty mind-blowing to realize that our own body hosts over 39 trillion microbial cells weighing approximately 1.5 to 2 kilograms!?

The microbiome is defined as the collection of all microbes, such as bacteria, fungi, viruses, and their genes, that naturally live on our bodies and inside us. The gut microbiome alone contains over 1000 species of bacteria, with their collective genetic material outnumbering human genes by 150:1!?

The microbiome is truly omnipresent in us. The majority of bacteria is residing in the gastrointestinal tract, but there are also bacteria in the skin, respiratory tract (nose, throat, and lungs), urogenital tract (vagina and urethra), oral cavity (mouth, tongue, and teeth), and even the eyes, forming unique microbial communities adapted to these environments.??

In the previous years I wrote a couple of brief news coverages about microbiome-related research and companies, but I was never truly interested in this topic up until this year’s 11th Aging Research and Drug Discovery Meeting (#ARDD2024) where I accidentally ended up listening to a lecture by Scotch McClure, CEO of Maxwell Biosciences: “Is Aging Contagious? Reviewing the known pathogenic drivers of degenerative aging.“??

A Texas-based biotech with prominent military contracts with the US government, Maxwell Biosciences is developing a broad spectrum antimicrobial capable of destroying viruses, fungi and bacteria with a single molecule. A bold claim, but how??

It appears, the human body naturally produces a peptide called LL-37 as part of its innate immune system. This peptide has broad antimicrobial properties and is effective against pathogenic bacteria, fungi, and viruses without harming beneficial microbes. However, LL-37 is unstable in the body, limiting its effectiveness against microbial invaders.

McClure's company, Maxwell Biosciences, has developed a synthetic version of LL-37 using what they call "peptoid technology." This synthetic version is stable and retains the beneficial properties of natural LL-37. The company is conducting various studies, including primate trials in the US and India, to test the efficacy of this compound and it is planning clinical trials in the first half of 2025.?

The synthetic version of LL-37 doesn't require refrigeration, has shown no development of antimicrobial resistance in studies, and reportedly has no adverse effects on the healthy gut microbiome. The company plans to deliver the drug as a nasal spray, which they claim allows direct targeting of the microbiome in the nasal cavity and brain.

But the company is not about only one lead molecule. Maxwell Biosciences is building an artificial intelligence (AI)-driven platform utilizing its CLAROMER? technology, designed to mimic the human immune system's natural antimicrobial peptides, such as LL-37.?

These synthetic peptoids (poly-N-substituted glycines) are engineered to target a wide range of pathogens, including viruses, bacteria, fungi, and biofilms, by disrupting their cellular membranes.

Considering the boldness of the idea of creating one (or several) molecules that would be effective against all known pathogens, I am looking forward to the upcoming clinical debut of the molecule in 2025. If successful, it would mean the era of universal antimicrobials might be well around the corner.?

Now, coming back to microbiome, the thing about it is that it can go out of order, what is called dysbiosis, and can have dramatic effects on our health. And, as I learned from McClure's presentation and some other follow up reading, on aging!?

The link between microbiome dysbiosis and disease became prominent when Helicobacter pylori was linked to gastric ulcers in the 1980s, reshaping our understanding of microbial influence on health. A healthy microbiome maintains balance by promoting the growth of beneficial bacteria (e.g., Lactobacillus) while suppressing pathogenic species (e.g., Clostridium difficile).?

Dysbiosis, whether through antibiotics, diet, or invading infections, can lead to diseases like inflammatory bowel disease, obesity, and even mental health disorders, emphasizing the delicate balance needed between healthy and pathogenic bacteria in our body.?

What’s more, research suggests that what happens when this balance is disrupted by pathogens, viruses, or bacteria from the outside world is that this chaos in the microbiome doesn’t just make us sick—it may accelerate the aging process itself.

For instance, dysbiosis can trigger inflammation, disrupt cellular communication, and impair the body’s ability to regenerate vital tissues. The result? The signs of aging—frailty, cognitive decline, and immune system deterioration—appear more rapidly.?

In his presentation during #ARDD2024, McClure went a long way explaining how microbiome dysbiosis might actually be a sort of foundational factor for all so-called Hallmarks of Aging.?

For those outside of aging research, Dr. Carlos López-Otín, a Professor of Biochemistry and Molecular Biology at the University of Oviedo in Spain, together with colleagues, introduced the concept of the hallmarks of aging in a landmark 2013 paper, categorizing aging into nine distinct biological processes.?

Now, McClure explained in his presentation that dysbiosis impacts all the known hallmarks of aging. These hallmarks include chronic inflammation, altered cellular communication, stem cell exhaustion, cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and disabled macro-autophagy.

While the research is still ongoing, McClure's work represents a novel approach to understanding and potentially intervening in the aging process through manipulation of the microbiome.

Basically, they approach aging research by focusing on immunosenescence, the age-related decline of the immune system. The goal here is to develop synthetic peptoids that mimic the function of natural antimicrobial peptides like LL-37, which decline with age and contribute to aging hallmarks such as increased susceptibility to infections and chronic inflammation. These biomimetic therapeutics are designed to restore immune system function, targeting and destroying a wide range of pathogens, including bacteria, fungi, and viruses, while also modulating inflammatory responses. In other words, Maxwell is building a path towards a “synthetic immune system.”

By focusing on restoring immune function and mitigating pathogen-induced damage, Maxwell is contributing to extending healthspan—the period of life spent in good health.

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-- Andrii