Profiling IntraClear, Aiming to Break Down Lipofuscin in Aged Cells

The Russian and Eastern European longevity community is quite active, with a number of non-profit organizations such as the Science for Life Extension Foundation and Open Longevity. There is arguably a greater interest in engineering greater longevity in that part of the world than in the English-language regions. That said, I would say they are behind the US-centric longevity community in terms of translating patient advocacy and scientific programs into startup biotech companies. Their successes to date include the clinical development of mitochondrially targeted antioxidants, the small molecule discovery company Gero, as well as less directly relevant groups such as the Estonian Haut.AI. Today, I'll note another Estonian project, IntraClear Biologics, an early stage venture focused on clearance of lipofuscin and other forms of harmful metabolic waste.

Lipofuscin is a collection of persistent metabolic waste compounds, not completely categorized and understood, that builds up in the lysosomes of long-lived cells in older individuals. This negatively affects the function of lysosomes, a critical component in cellular maintenance, responsible for breaking down unwanted molecules and structures in the cell. Lipofuscin aggregation is a combination of age-related lysosomal dysfunction, coupled with the slow generation of persistent metabolic waste that cannot be effectively broken down even by functional lysosomes. One part of the SENS rejuvenation biotechnology agenda is clearance of lipofuscin in order to remove its damaging effects on cellular recycling and maintenance. So far not all that many groups are working on projects in this space, unfortunately.

I have seen more of the IntraClear materials than are discussed in the article here, and they have an ambitious program in mind, developing clinical assays to determine lipofuscin burden, while in parallel conducting drug discovery for therapies capable of degrading the persistent lipofuscin compounds that build up in old cells. The challenge is, as every, convincing someone to fund this approach to rejuvenation past the initial seed stage. Someone will have to: lipofuscin clearance is a broad topic, and it is clearly an important contribution to degenerative aging, particularly in the central nervous system where there are many long-lived cells. There are a lot of different problem molecules in the aggregated mess of metabolic byproducts given the name lipofuscin. This could keep a number of companies busy for quite some time. LysoClear, for example, is focused on clearing only the A2E found in retinal lipofuscin.

Bioengineering longevity: call for open source approach

With an advisory board packed with longevity firepower (including Aubrey de Grey of the SENS Research Foundation, James Clement of Betterhumans and Gary Hudson of Oisín Biotechnologies), IntraClear Biologics is on a bioengineering longevity mission to "help humanity win the war against age-related diseases." IntraClear is based in Tallinn, a city often dubbed the European Silicon Valley due to Estonia's Government's innovative policies and education initiatives and the fact that it has one of the highest start-ups per capita rates in the world. With a research programme that includes developing a therapy for the removal of intracellular junk from the human body and developing a comprehensive panel of primary aging biomarkers, we were keen to talk to their Chief Science Officer, Ariel Feinerman, to find out more.

Feinerman attributes IntraClear's origin to three influences: Dr Aubrey de Grey who really sparked his interest in longevity, physician Alexander Morozov from Belarus, who drew his attention to lipofuscin and Yevgen Haletskyi from Kiev, Ukraine who listened to Feinerman and Morozov's lectures and became interested in their programme. Haletskyi offered support and angel investment and IntraClear, with Haletskyi as its CEO, was born.

IntraClear is built around lipofuscin, common intracellular junk which is a fluorescent complex mixture of highly oxidised cross-linked macromolecules like lipids, sugars, proteins, and heavy metals ions. "Even though lipofuscin has been known since 1912, researchers don't fully know its composition and structure. Lipofuscin accumulates in all cells of the body, especially in the skin, brain and muscles, it inhibits proteasome and has cytotoxic effects. The accumulation of lipofuscin is associated with many aging pathologies, like neurodegenerative, neuromuscular, inflammatory, etc, and it heavily causes skin aging. Our idea is simple but powerful. Our gene therapy will have two parts: mRNA from which cells can synthesise lipofuscin-breaking enzyme and a fusogenic liposome as a vehicle." IntraClear is considering licensing the liposome vehicle tech Fusogenix from Entos Pharmaceuticals, but is also considering developing its own vehicle to ensure passage across the blood-brain barrier.

"It is particularly interesting how we will obtain the enzymes. Firstly we will isolate lipofuscin from human tissues. Because lipofuscin is likely specific in each tissue we focus on the skin, muscles, and brain, but if we cannot isolate lipofuscin using current technology, we will use physical methods like nanoscale NMR to investigate lipofuscin in vivo. This is avery promising, although emerging technology, so we need to improve it ourselves. After we investigate the structure of lipofuscin using a variety of methods, we will use metagenomic analysis to search for bacteria which have lipofuscin-breaking enzymes."

IntraClear Biologics

As a result of normal metabolism, many by-products are formed in our body. Normally, almost all such products are removed using various repair mechanisms. However, some of them cannot be removed from the cells and extracellular space. Over time, they accumulate and lead to disruption of the normal function of cells and tissues, impair the metabolism and cause various diseases. Currently, our group is conducting a histological study of skin tissues, muscles (including heart), brain, and liver. We study lipofuscin granules in the materials. Based on the results of this stage, a histological atlas (virtual/physical) of lipofuscin content in different tissues in people of different ages/sex/with different chronic diseases will be released.

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