In the first post in this series, we discussed the quest for a longer and healthier life and how unproven approaches are dominating this commercial markets right now. Beyond the preventive measures involving lifestyle changes and certain medications to help manage or prevent chronic diseases (e.g., GLP-1 medications) we don’t have any breakthroughs yet in arresting or reversing the biological aging process. That, however, doesn’t mean that there is not active research going on. In fact, I named a few key areas that are the focus of intense research, including epigenetic and cellular reprogramming. Given the progress made in advancing our research methodologies and the arrival of AI, there is reason for optimism in the medium- to long-term.
The recent wave of optimism in this area is growing out of the progress made in our research into epigenetics and cellular reprogramming, which have greatly improved the scientific understanding of aging over the past 20 years. In 2006, Shinya Yamanaka demonstrated the ability to reverse cell differentiation for the first time, effectively reversing a cell back into its embryonic-like state. That means the cell could now be programmed to function in different capacities in the human body. Cellular reprogramming, as this technique is called, has been used to turn human skin cells into multiple other cell types, including neurons, and is being applied clinically to regenerate retinal cells damaged by age-related macular degeneration. This research led to subsequent progress in understanding how DNA methylation patterns (epigenetics) are part of the aging process and the concept of epigenetics clock theory of aging is now well accepted. In mice models, applying of these techniques has led to extending life by 30% and preventing or delaying chronic diseases. There is now a growing number of companies that are trying to bring this to human research and extend human life and prevent disease.
The most recent research in epigenetic reprogramming involves partial reprogramming that preserves the cell type but changes the epigenetic marks by delivering transcription factors (proteins) into the target cells. This relies on viruses as vectors that can be given to patients and then travel to the target tissue and cell type and deliver the therapies that will do the reprogramming. It seems that the early applications of this may involve recovering function in specific organs such as kidney, liver, immune system, and more. This may extend to reprogramming healthy but aging cells and thus reversing biological aging and preventing disease. Another promising approach to prevent or delay disease is through senolytics. These are drugs that clear out old cells that are not performing useful functions in our bodies but are secreting harmful substances that can lead to inflammation and downstream issues like cancer and chronic diseases. While this is not a classic cellular age reversal agent like epigenetics reprogramming, it, in effect, delivers a similar outcome of preventing age-related diseases.
All of this is complicated science and it is to be expected that it will be years before we can expect tangible aging reversal in humans. Finding the right targets for the transcription factors that reprogram the epigenetics, developing those factors, and building the right vehicles to deliver them to the right cells takes time. Then, you need to do the long trials to show that the therapies had the intended effect. What endpoints are acceptable is a matter of debate. Can you show younger cells inside the body and call it a day? or, do you need to show a lower incidence of chronic diseases in the treated population? That would take years and decades. Investors are usually not that patient and want to see a healthy return on their investment in a reasonable time frame. Public sector investment in this area will be critical since that is patient capital that does’n’t require a return on investment in 3-5 years. The issue of ROI has been a salient in these emerging fields, where the potential payoff can be huge (who wouldn’t spend money to live longer and healthier?) but the road to finding proven therapies is long and risky. That brings us back to the issue I discussed in the first part of this longevity series: companies making claims about products that have longevity benefits without any evidence. If supplements are being prescribed based on analyzing your genes or microbiome and the touted benefits are being healthier or living longer, where is the hard evidence?
Given the amount of biological entities in our bodies (e.g., genes, microbiome, mitochondria, etc) and the need to understand their function and also how these parts contribute to the functioning of an organ and how that organ contributes to the overall organism (i.e., a human!) this research is not easy. Learning about the biological entities inside our bodies and developing ways to study and measure them is a starting point. But, once you do that, now you have billions and trillions of entities and all of the interconnectedness between them that you have to understand. This is why this type of research is hard and slow. However, with the emergence of machine learning, we have a new and powerful tool in this fight. The major advantage of AI over previous analytic methods is that it can handle more data and complex data. That’s exactly what we deal with in human health research. If computational biology can now accelerate our quest to understand the human body, it can potentially shave years and decades from our wait time to find the best longevity solutions. Recent experience with using AI in studying genetic targets for transcription factors that can reprogram the epigenetics or designing the best transcription factors seems to indicate that AI can be a difference maker for achieving breakthroughs. A growing number of companies are exploring the applications of reprogramming and senolytics in neurological diseases (e.g., dementia, parkinson’s,) cardiovascular diseases (e.g., heart failure, vascular disease,) cancer, immune system decline, and more.
There is now also significant research in addressing multiple age-related issues by slowing or reversing the systemic process of aging that affects different cell types and organs. By targeting core aging mechanisms—such as senescence, chronic inflammation, and mitochondrial dysfunction—a single intervention, such as senolytics or reprogramming, might concurrently improve immune system and prevent dementia. This paradigm shifts disease- and organ-specific research to finding treatments to systemic aging process, addressing multiple age-related conditions through unified biological pathways. Given the emerging nature of this type of research, there is not necessarily historic precedence for how you run the clinical trials and which endpoints can be used to establish the validity of the approach, since demonstrating anti-aging effects demands decades-long trials.
So, while the current crop of companies selling supplements for longevity based on the AI analysis of your genes or microbiome are not on solid scientific ground, there may be a future (hopefully not too distant) that such approaches would be possible and legitimate. It is important to keep in mind that many promising approaches in animals do not translate to benefits in humans. As such, it is important not to buy into the hype of a promising approach that may never deliver results in human. It is critical to expect high-quality human studies to validate claims made by commercial entities and for those studies to have been done by academic medical centers.
