Aldring er en del av livet – men det betyr ikke at vi ikke kan kjempe

Fra kreftbehandling til lang levetid

Aldring og lang levetid er veldefinerte biologiske prosesser knyttet til opphopning av senesente (aldrede) celler. Og en modifisert kreftbehandling kan bidra til å reversere denne prosessen.

Corina Amor Vegas, assisterende professor ved Cold Spring Harbor Laboratory (CSHL), har klart å modifisere en immun hvit celle (T‑lymfocytt) slik at den angriper senesente celler. Denne prestasjonen ga henne en plass på Forbes 30 Under 30 Europe‑listen 2022.

For å gjøre dette, ombrukte de en teknologi kalt CAR‑T (Chimeric Antigen Receptor T‑celler). CAR‑T brukes vanligvis i kreftbehandling slik at de modifiserte T‑cellene kan angripe kreftceller. Denne evnen til spesifikt å målrette en unik celleprofil i kroppen kan i dette tilfellet ombrukes til å fokusere på aldrende celler i stedet for kreftceller.

Disse senesente cellene anses som en hovedårsak til aldring hos pattedyr og forårsaker systemisk betennelse etter hvert som de akkumuleres over tid.

Turning CAR‑T cell into an anti‑aging treatment in mice resulted in:

• lavere kroppsvekt
• forbedret metabolisme og glukosetoleranse
• økt fysisk aktivitet

Another impressive aspect of using CAR‑T is that it could be a lifelong treatment. Targeting senescence is not a new concept, but previous approaches had mostly focused on drugs, which would require regularly taking a pill or an injection. This could prove too expensive, inconvenient, or increase the risks of side effects.

In contrast, T cells have a long memory and can “learn” from each other. So CAR‑T therapies can have effects lasting many years. A perfect match for chronic disease, which is what aging is increasingly considered, instead of a fatality.

De mange veiene til lang levetid

While Prof Vegas’s research on CAR‑T is promising, this is not the only path researchers are looking into to improve human longevity. Other approaches are focusing on rejuvenating aging cells instead of targeting them.

We know for a fact that it is possible for an “old” cell to become young again from a metabolic and genetic standpoint. This is actually something happening each generation, with the first cell of new embryos being “reset” when it comes to aging.

There is an argument to be made that aging is something that evolved instead of just being a byproduct of accumulated damages (the theory of evolvability, in contrast to other theories about the evolution of aging).

In that context, aging is seen as a mechanism that was selected by evolution. And if that’s the case, it is a mechanism that could be turned off, and is an idea that has gained momentum in the last 10 years.

Kilde: Nature.com

Epigenetisk foryngelse

For a while now, researchers have found ways to turn adult cells into immature, embryo-like cells, a technology called induced-Pluripotent Stem (iPS) cells. While this can help for some tissue therapies and repairing damaged organs, such undifferentiated cells are not ideal and could even cause cancer.

For an aging cure, a better option would be to reboot the cells to a more youthful state but keep them differentiated.

This is the process of epigenetic rejuvenation. It brings back to a “young state” the modifications done to the genome (epigenetic) that cause aging by changing the gene expression profile. Among the genome modifications with age are DNA methylation, histone modifications, chromatin remodeling, and RNA modification.

Kilde: Nature.com

One way to perform epigenetic rejuvenation is through active small molecules. These tend to be organ or tissue-specific, so a full body rejuvenation might be a cocktail of molecules.

Kilde: Nature.com

Another option is using the same general method for creating induced-Pluripotent Stem (iPS) cells. But instead of doing long‑term reprogramming (with the associated cancer risks), targeting a transient reprogramming, often through an mRNA‑based method, is not entirely different from mRNA vaccines. But instead of a virus antigen, the mRNA is used to produce for a short period of time a rejuvenating/reprogramming factor.

Telomer‑tilbakestilling

Telomeres are a specific genetic sequence at the end of each chromosome. It has long been known that telomeres get shorter and shorter with aging, and this is especially true in damaged or aging cells. Hence, the idea of growing back telomere to fight aging.

Kilde: Wikipedia

This idea was reinforced when it was discovered in 2015 that telomere extension in human cells made them “behave” like much younger cells. This, too, was achieved by using modified mRNA. In 2020, it was found that small molecules could also achieve this result.

Unfortunately, managing to modify telomeres inside the body of patients has proven harder than in cell cultures. Combined with the necessity for telomere regeneration to be transient (to avoid cancer risks), this has made telomere resetting somewhat lag compared to epigenetic rejuvenation.

Livsstil‑ og metabolske endringer

It is, of course, known that a healthy lifestyle can help you live longer. But this idea can go further.

For example, it has been proven that caloric restrictions (eating less energetic food) can dramatically expand the lifespan of lab mice. More interestingly, caloric restrictions (40% fewer calories) in monkeys, our close evolutive cousins, have also shown a much younger profile of blood methylation.

Undisturbed circadian cycles (sleep & rest) and regular exercise have also been shown to impact epigenetic changes like DNA methylation.

So while optimizing our genetics and resetting the age of existing tissues is probably the path to true life extension, lifestyle and diet should also be important considerations when discussing longevity.

Omvendt ingeniørkunst av naturen

Aging is a very common occurrence in animal species, but not every species. For example, a jellyfish called Turritopsis Dohrnii is, for all practices and purposes, immortal. When facing physical damage or starvation, it reverts back to a polyp, a larval/embryo stage of jellyfish development. This shows that there is no theoretical limit to how much an animal can rejuvenate itself.

Of course, humans are much more complex organisms than jellyfish. But vertebrates can live very long, too. Greenland sharks are able to live at least 250-500 years, as long as they are not injured and find enough food. So, some of these sharks might have been around since when the first European sailors discovered the Americas.

The Greenland sharks make for an interesting study, as they do not display any of the common features among most long‑lived animals:

• Små eller enkle organismer som maneter eller muslinger.
• Lav aktivitet som skilpadder.
• Planteetere som elefanter.

Sharks, in general, are also known to show very low to null cancer rates and neurodegenerative diseases. So, understanding their genetics could allow us to replicate in humans what is working in sharks.

A daring expedition of researchers from Czechia into Icelandic water, dealing with frigid temperatures, sharks, and even earthquakes and volcanoes, went to collect genetic data. They discovered that Greenland water has unique p53 and H2AX proteins, both proteins that have previously been linked to changing longevity.

In the very long term, it is possible that we find how to modify our bodies permanently to imitate the longevity and resistance to cancer and diseases of Greenland sharks. So, while it is a more distant prospect, the science‑fiction idea of genetically modifying the human race to achieve casually centuries‑long lifespans might be a reality sooner than expected.

Aksjer med fokus på menneskelig lang levetid

1. Longeveron

Longeveron jobber med celleterapier for reparasjon av skadet vev, degenerative sykdommer og effektene av aldring.

Hovedteknologien deres er Lomecel‑B™. Dette er celler samlet fra donorers benmarg, selektert og deretter masseprodusert. De er multipotente celler kalt medicinal signaling cells (MSCs) med kapasitet til å reparere skadet og/eller betent vev.

Kilde: Longeveron

The company pipeline is focused on 3 different applications for Lomecel‑B:

• Hypoplastisk venstre hjerteklaffsyndrom (HLHS), en medfødt fødselsdefekt.
• Alzheimers sykdom.
• Aldersrelatert skrøpelighet, en lavgradig kronisk pro‑inflammatorisk tilstand adskilt fra normale aldringseffekter.

Early clinical trial results seem to indicate an increasing survival rate for HLHS, a dose-dependent improvement of aging frailty, and improved cognition and quality of life in Alzheimer’s patients.

Lomecel is a stem cell‑based method looking to reverse aging or regenerate damaged tissues. This approach seems successful and shows that aging could be at least be partially corrected with the replacement of damaged cells by “fresh” stem cells.

2. Lineage Cell Therapeutics

Lineage produserer 200+ forskjellige menneskelige celletype for implantasjon, med start i pluripotente celler og ved bruk av en proprietær guidet differensieringsmetode.

Lineage har 2 potensielle produkter godt avansert i fase 2 av kliniske studier, og 3 andre i en tidligere fase.

Kilde: Lineage

Flaggskipproduktet er OpRegen, i partnerskap med Genentech, som behandler øyeproblemer, inkludert aldersrelatert makuladegenerasjon (AMD). Lineage mottok $50 M fra Genentech på forhånd og er berettiget til $620 M i milepælsbetalinger og tosifrede royalties. Den innledende studien oppnådde enestående retinal regenerering for 5/12 pasienter.

Det andre, mer avanserte programmet er OPC1 (Oligodendrocyte Cell Transplants) for ryggmargsskade. Behandlingen kan bidra til å beskytte ryggmargen og dramatisk redusere antallet pasienter som ikke viser forbedring. De første resultatene har vært oppmuntrende, med mange pasienter som gjenvant følelser de sannsynligvis ikke ville ha hatt uten behandlingen.

Kilde: Lineage

“Jeg kunne ikke drikke, kunne ikke mate meg selv, kunne ikke sende meldinger eller egentlig gjøre noe, jeg eksisterte bare. Jeg levde ikke livet mitt, jeg eksisterte.” – Kris Boesen, OPC1‑pasient

In the long run, the VAC platform could be very promising as well. Not only could it help to fight cancer, but it could also be deployed to create immunity against infectious diseases.

3. MeiraGTx Holdings

MeiraGTx er et gen-terapifirma med fokus på aldring og bruker adeno‑associated virus (AAV) som vektor for å levere gener. Fokus på AAV gjør at selskapet kan utvikle svært tilpassbare terapier for ulike patologier og celletype.

“Lette forskjeller i kapsidproteiner kan modulere effektiviteten som ulike kapsider leverer gener til ulike celler, og dermed tillate at forskjellige AAV‑kapsider velges for mest effektivt å målrette bestemte celletype.”

The technology also comes with an on/off “riboswitch” that activates the gene added to the patient’s body on demand, giving an extremely high level of control over the gene therapy.

The company is active in 3 therapeutic fields: ocular, neurodegenerative (including Parkison’s disease), and salivary gland diseases.

In desember 2023, MeiraGTx entered into a $415M asset purchase agreement with Janssen for its X‑linked retinitis pigmentosa (XLRP) treatment. The company also has 2 other ongoing ocular clinical trials in partnership with Janssen.

Kilde: MeiraGTX

The extreme level of control over the activation of the gene therapy of MeiraGTx technology could be highly relevant for future longevity therapy. We could imagine CAR‑T or epigenetic regeneration effects to be modulated this way, reducing the risks of unwanted side effects often hindering the prospects of anti‑aging therapies.

This is clearly something in the company’s targets, as it is already working on a ribo‑CAR system, with immune cells activated on demand by the riboswitch technology, in a dose‑dependent manner, which could also be deployed for CAR‑T therapies in cancer treatment.