As Rejuvenation Research Expands,We Need to Focus on Identifying the Most Effective,Safest Approaches

The first step in rejuvenation research was and continues to be the foundation of understanding aging. The scientific pursuit of the principles and mechanisms of aging spans millennia, and the journey clearly continues, as this understanding is fundamentally and critically relevant for our lives.

At the same time, there are already candidates and clinically applicable approaches, which have been proposed to have the capacity to attenuate aging and reduce the risks of age-associated diseases, also known as the comorbidities of aging. Single molecules, such TIMP2, rapamycin, metformin, PF-4, ¹ exercise-released systemic myokines and other positive factors, the transient expression of various combinations of Yamanaka factors and/or their inducers, ² and on the other side of the coin, the dilution or neutralization of systemically age-elevated proteins, ³ such as senolytics, senomorphics, are among the approaches which have become of interest to biotech as potential rejuvenative products.

Questions remain as to whether and to what degree the published rejuvenative approaches might meaningfully increase human health-span, as opposed to applying only narrowly to a specific experimental system. Many proposed rejuvenative approaches have been tested in a limited experimental set-up, mostly with animals or 2D cell cultures, and the analyses often have natural bias to highlight the positives. As mentioned in my previous editorial pieces, positive self-propagated viewpoints on research outcomes have sadly become a trend in past decades. This might be due to limited research funding in the aging field and because negative data that show experimental hypotheses to be wrong or even weak, are notoriously difficult to publish or to fund a study into what did not work and why.

On the surface, we are quite successful in publishing cures of aging parameters or symptoms; however, clinical trials on the efficacy are failing or are not even in progress. This lack of advance is, interestingly, simultaneous with the glowing popular press that often suggests that “this is it”—a magic bullet to strike down aging for a long heath-span. ChatGPT's answer about hurdles of rejuvenation research would likely be that based on popular there are no hurdles, and we are almost at the finish line.

The many profoundly interesting articles in rejuvenation research still represent work in progress that deserves to be highlighted as such. Unfortunately, some try to biohack published approaches (at times, verbatim) without an in-depth understanding of the figures, results, and limitations, basing their decision on the title, abstract, popular press or the positive reviews and perspectives.

The in-depth evaluation of research papers is not easy as it requires multiprong expertise that are not only sufficiently deep in one area but also often needs to be multidisciplinary. For example, most top-notch recent articles combine biomedical experiments with advanced bioinformatics and computational science such as machine learning. Accordingly, when the articles are discussed at Journal Clubs of research laboratories, the limitations are often clear because the details of the figures, results, and methods are well understood. Another advantage of evaluating published work from the standpoint of multidisciplinary scientific expertise is our ability to compare-and-contrast each article with the body of work in the field and to perform a reality check.

To give an example, a popular and very interesting work in progress on the Machine Learning clocks that aim to linearly predict age and health/disease, typically, by Elastic Net Regression, show the clocks lose biological accuracy and do not distinguish health from disease well, specifically because the data are adjusted by biologically arbitrary weights to fit it onto a hypothesis of linearity. The understanding, diagnostic, measurement of biological age, and intervention into this process, critically depend on data supporting that neither aging not disease are linear processes. ⁴

In another example, in heterochronic parabiosis, not only blood but also organs and environments are shared, which is a limitation of this method. Old animals benefit from young lungs—oxygenation, young gastro-intestinal tract—nutrition, young kidneys and liver—waste removal, young immune system—combatting infections, cancers, and clearing wounds. The rejuvenative life extending effects of parabiosis on old rodents ⁵ as well as pro-geronic effects on young parabionts are known since mid-last century and are well reproducible ⁶ but cannot be clearly attributed to the endocrine factors in blood, after blood vessels grow between the young and old surgically joined animals. And, in a reality check, dilution of old blood plasma, without young blood or factors, is robustly and quickly rejuvenative, ⁷ in mice and in people. Conversely, exchanging young mice with 50% of old blood makes them old and senescent within 2 weeks, and that is with all their young molecules, cells and 50% of their young blood. ⁸ How can young blood factors rejuvenate an entirely old mouse or person?

Regarding side effects, not just the four Yamanaka genes together but also each separately is associated with human cancers ⁹ ; elimination of these dangers by transient expression remains at the earliest level of study. Other abovementioned rejuvenative candidates (molecules and approaches) also associate with cancer, or inhibit immune system, or induce fibrosis ¹⁰ or are causal to age-related loss of angiogenesis ¹¹ or promote ministrokes/blood clotting, or activate complement system, etc., or other undesired outcomes. These and other side effects that are less known and studied but predicted from the mechanisms of action of rejuvenative candidates, need to be solved before their use in meaningful rejuvenation.

Rejuvenation Research perceives a solution to the above-discussed conundrum. It is clearly important to penetrate the difficult science of the excellent work in progress, providing not just the well-deserved and important thumbs-up cheers for good research but also outlining the limitations and remaining questions, to focus on overcoming these in future research—the next steps.

Accordingly, our expanded focus will include publishing critical reviews of the field, enhancing and disseminating the understanding of the drawbacks, inherent in the known mechanisms, or limited by the experimental systems, or less well defined and requiring dedicated research before being resolved.