The company Ponce De Leon Health claims that a recent pilot study of calcium alpha-ketoglutarate supplementation results in an average reduction of 8.5 years of epigenetic age via the DNA methylation test offered by TrueMe Labs. This being the supplement industry, expect to have to wade through a lot of dubious and excessive marketing to find any solid information about what actually happened here. The best pace to start is with the 2019 paper on the effects of calcium alpha-ketoglutarate in mice, which is a reputable study authored by reputable researchers. Delivered late in life, this intervention reduced frailty to a meaningful degree, but with only a modest effect on life span. It did not reduce senescent cell burden, but did reduce inflammatory signaling – and chronic inflammation is an important aspect of degenerative aging.
The important point to consider here is that the TrueMe Labs assay is not a relabeling of any of the more established epigenetic clocks, those with significant research associated with their behavior. It is is its own beast, an independently developed test. It uses only 13 DNA methylation sites, and so it is very possible that it is much more sensitive to some interventions than others, in comparison to, say, the original Horvath clock, depending on which mechanisms influence those sites. Thus one cannot take any of the established research into the better studied clocks and use it to inform expectations as to how the TrueMe Labs assay will behave. 8.5 years might sound like a large effect size, but it is impossible to say whether or not that is the case.
That is the challenge with all epigenetic clocks, frankly. None are yet strongly connected to underlying mechanisms of aging; it is hard to say what any specific change or outcome actually represents in terms of metabolic processes. The assays will produce a number, but that number cannot be compared between clocks, and it cannot be compared between interventions. It cannot even be used to say how good any specific intervention might be, without a great deal of further calibration for that specific intervention. Not that one would learn that by reading the Ponce De Leon Health marketing materials. A cynic might suggest that they shopped for the clock that would produce the most sizable outcome for their intervention. Whether or not that is the case here, I’m sure that this strategy will become prevalent.
Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes.
Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.
Ponce de Leon Health initially worked with Dr. Brian Kennedy, who was, at the time, based at the Buck Institute for Research on Aging, searching for compounds that were generally recognized as safe (GRAS) but that had the potential to influence aging in mammals. The company screened over 300 GRAS compounds and identified compounds that could modulate a number of pathways that are linked to aging. Dr. Kennedy subsequently joined Ponce de Leon Health as its Chief Scientific Officer, and the company has been busy testing and preparing to translate these findings to people. Its strategy has been to test its products on mammalian models that closely emulate human aging in order to give the best chance of translating beneficial results to us.
For consumer testing the company gave participants Rejuvant and measured their epigenetic ages using DNA methylation testing. This supplement contains a proprietary form of calcium alpha-ketoglutarate, which the FDA considers to be GRAS. The company believes that Rejuvant works by slowing down the rate of age-related DNA methylation and reducing the inflammation caused by senescent cells, two proposed reasons why we age.