A Trial of Proprietary Epigenetic Age Assessments, With No Other Attached Health Data, Provides No Value
You'll recall that a collection of research groups and companies are working to assess the benefits of alpha-ketoglutarate supplementation. The results reported to date focus exclusively on outcomes in epigenetic age assessment, using a proprietary clock algorithm that is not yet open to inspection or analysis. The open access paper I'll point out today is the formal publication of the results announced earlier this year. Since no other information on patient outcomes beyond epigenetic age is provided - such as, for example, measures of inflammation, immune health, and so forth - this data is essentially of no value whatsoever. The earlier mouse studies were more informative! We cannot even speculate as to what this particular epigenetic clock is measuring. Not that we could do much better given the clock algorithm, once it is published: it is presently impossible to make more than sketchy reasoned guesses at what fully described epigenetic clocks such as GrimAge are actually measuring.
Since epigenetic clocks are discovered in epigenetic data via machine learning processes, at present no-one knows how or why the identified characteristic epigenetic changes arise with age. Thus no-one can guess in advance as to how a specific epigenetic clock will react to any given intervention that affects only a subset of the processes of aging. To be useful as a means of rapidly assessing whether or not a given intervention is actually producing rejuvenation, an epigenetic clock must be first calibrated against that intervention by running life span studies in mice. Alternatively it must be established as to exactly how these epigenetic marks relate to underlying processes and consequences of aging. The former is an easier task, but still an expensive one.
Cynically, it is clear that people in the marketing-dependent supplement space are going to skip the question of understanding in favor of simply shopping for large numbers. They are going to run different clocks against all of the cheap, low-yield approaches known to upregulate cellular stress responses or reduce inflammation and publicize the largest reduction in epigenetic age regardless of the merits of the approach and the clock. There will be a lot of this sort of thing going on in parallel to more responsible work that is focused on gathering enough data to start to say something useful about how these epigenetic clocks work. The mark of a responsible study is, I think, the presence of a lot of other comparison data from study participants, such as measures of frailty, inflammation, and other markers of aging and age-related disease. That is clearly not the case in this paper.
The epigenetic clock is an attractive biomarker of aging because it applies to most human tissues, capturing aspects of biological age such as frailty, cognitive/physical fitness in the elderly, age-acceleration in obesity, and lifetime stress. Markers of biological aging represent an important tool to clinically validate the effects of longevity-based interventions. For the first time, these biomarkers of aging give scientists the opportunity to study the effects of anti-aging compounds in real-time and directly in humans. We utilized the TruAge prediction model with Sanger sequencing for DNA methylation analysis. In total, 3 genes including 9 CpG sites were analyzed by the Sanger sequencing. The DNA methylation values obtained for all CpG sites were included in the TruMe age-prediction model (pending publication).
Alpha-ketoglutarate (AKG) is an endogenous intermediary metabolite in the Krebs cycle whose levels naturally decline during aging. AKG is involved in multiple metabolic and cellular pathways. These include functioning as a signaling molecule, energy donor, precursor in the amino acid biosynthesis, and a regulator of epigenetic processes and cellular signaling via protein binding. AKG deficiency in stem cells and progenitor cells increases with age. As animals age, mitochondrial function is progressively impaired and cellular metabolic flux in the mitochondria declines, which exacerbates AKG deficiency. It was reported that AKG increased the lifespan of C. elegans.
Building on these results, AKG (and calcium salt) combined with other Generally Recognized as Safe (GRAS) compounds were studied in mice. The non-genetically altered mouse is the preferred mammalian model to study aging, since the biochemical processes involved in mice aging may apply to other mammals, including humans. In a recent study, sponsored by Ponce de Leon Health and performed at the Buck Institute for Research on Aging, the effect of alpha-ketoglutarate (delivered in the form of a calcium salt - CaAKG) on healthspan and lifespan in C57BL/6 mice was reported. The authors showed that in the mice, AKG reduced frailty and enhanced longevity, indicating a compression of morbidity. These and other discoveries suggest that AKG may be an ideal candidate for pro-longevity human studies.
Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNA methylation testing was performed at baseline and by the end of treatment with Rejuvant supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years using the TruMe age-prediction model. Furthermore, the supplementation with Rejuvant is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.
Clocks are just clocks. Like year rings on a tree and deciding the chance it will fall next year. It is a very good predictor because it well correlated with the chronological age. But it doesn't really tell much about the health of the said tree. Or the mileage odometer on my car. For some older models after you travel more than 999999 miles they were reset to 0. Not a great predictor if you tamper with the clock.