Fight Aging!

The long-running yearly Aging Research and Drug Discovery Meeting (ARDD) in Copenhagen is five long days of presentations from academia and industry, focused on the development of therapies to treat aging in some way. That largely means efforts to manipulate metabolism in order to slow down the progression of aging, but there are always those who seek to repair forms of molecular damage in order to produce some degree of rejuvenation. The sheer number of presentations, and the multiple tracks, means that any commentary on ARDD can really only pick one presentation in ten to discuss at best - which is much the case here.

Michael Ringel of Boston Consulting Group gave a deep and fascinating talk on the evolutionary origins of aging. Geroscientists are mostly focused on how aging happens, but why it happens is also important. Several theories have been proposed. According to Ringel, those explanations can be divided into three broad categories: Mechanistic, Weakening Selection, and Optimization. The first one posits that aging happens due to the inability of evolution to eliminate physical constraints such as the damage that arises from normal biological processes. Basically, miracles don't happen. The second one means that, as organisms age and survival declines, there is less evolutionary pressure to maintain the traits that would keep them healthy later in life. Selection becomes so weak that random mutations, including those that accelerate aging or cause diseases, are no longer removed effectively from the gene pool. This allows aging and late-life deterioration to persist in the population. Michael argued that current empirical evidence is best explained by the optimization paradigm. This has an important implication: a vast majority of pro-longevity mutations, just like other mutations, are a step away from that carefully optimized state. If you look at a broader context of reproductive fitness, you will probably find how it is hurt by the mutation.

Some longevity biotechs don't shy from making big claims, and Maxwell Biosciences is one of them. Its goal is to create "a synthetic immune system" that would give us wide protection against microbial pathogens. Bacteria and viruses evolve quickly, developing drug resistance. Fungi can wreak a lot of havoc and are understudied. The body has defense mechanisms, but they dwindle and get overwhelmed as we age. One such mechanism is the antimicrobial peptide LL-37. Maxwell's LL-37-mimicking candidate kills viruses and bacteria by permeating their membranes and is effective even against highly resistant bacterial strains. Maxwell runs several high-profile collaborations and is wrapping up a study in rhesus macaques with results expected later this month. Human clinical trials will begin next year.

John Sedivy of Brown University reminded the audience that about half of our genome consists of repeated sequences, mostly transposons associated with viruses. While some transposons are benign "viral fossils" that lost their ability to replicate, a majority can still do it if the patches of the chromatin where they are located are derepressed. Transposon reactivation increases with age and has been linked to multiple age-related conditions. This can happen in a positive feedback loop: cellular senescence leads to chromatin opening, LINE-1 (the most ubiquitous retrotransposon) derepression, antiviral response, and then to chronic inflammation. Transposon Therapeutics, the company that John advises, is built on the idea that we can use existing reverse transcriptase inhibitors (such as anti-HIV drugs) against age-related retrotransposon activation. Studies in animal models show that these drugs can have a massive effect on inflammation, cellular senescence, and age-related cognitive decline. The company is already deep in clinical trials with censavudine, a reverse transcriptase inhibitor.

Link: https://www.lifespan.io/news/for-the-11th-year-in-copenhagen-highlights-from-ardd-2024/