Hi Friend,A new study is out: things that make you age faster, and slower, according to 16 epigenetic age clocks.These interventions demonstrated a significant decrease or slow-down of Biological Aging1. Pharmacological Interventions: Anti-TNF therapy (anti-inflammatory), Metformin (Anti-diabetes, AMPK activation), Ketamine (antidepressant psychedelic, dissociative). 2. Supplements: AC11 supplement (natural DNA repair booster), TruLacta (a human-milk based supplement).3. Lifestyle Adjustments & Surgeries: Gastric Bypass (weight reduction), smoking cessation, kidney transplant, hyperbaric oxygen therapy HBOT (large average effect, but no statistical significance)4. Diets: Vegan Diet, Green Mediterranean Diet, Mediterranean Diet, low fat and low carb diets.These interventions demonstrated a significant increase or acceleration of Biological Aging1. Pharmacological Interventions: Rapamycin (mTORC1 inhibitor, immunosuppressant), senolytics.2. Supplements: Buckwheat Extract 3. Gene Therapies: Follistatin (myostatin inhibition, muscle growth)4. Lifestyle Adjustments, procedures & Surgeries: Kidney DialysisThe findings are very reassuring regarding my health program and the Blueprint stack and some of the latest changes we introduced.Many of the reported findings echo my protocol and system, which is fascinating as it indicates that continuous measurement and optimization for actual biomarkers and performance indicators automatically consolidates the interventions that best slow down epigenetic biological age.Here are some examples:RapamycinIn September I stopped Rapamycin, based on concerns around its metabolic side-effects observed in my lab results (including increased cholesterol, blood sugar and RHR); the data here showed Rapamycin increased biological aging according to two clocks, while ineffective according to the others. Details here.MetforminI continue to take Metformin, despite concerns based on its ineffectiveness in ITP mouse studies (2), and claims about it blunting muscle growth (3) (I am top 0.1% of my age-group for muscle volume) evidence from this study and from aging clocks in non-human primates (4), as well as lowering cancer incidence in retrospective population studies (5), all indicate metformin as a promising longevity intervention.DietA green mediterranean diet fared best at reducing/slowing down aging as measured by 10 out of 16 aging clocks, this diet is the closest to my Blueprint diet. Also, I stick to a grain-free diet. The slight but significant acceleration in aging clocks observed with buckwheat extract further validates the choice of avoiding grains.Follistatin gene therapyThe study reported a significant increase in biological age with Follistatin gene therapy, primarily driven by its effect on the PACE aging clock. I have received this therapy, which successfully boosted my circulating Follistatin levels. Upon getting the gene therapy my PACE score dropped from 0.70 to 0.64. While this effect is associative, and is not necessarily caused or driven by the increase in my Follistatin, it is still reassuring that - at least in my case- Follistatin gene therapy had no undesired effect on my biological age. We remain very curious about the reported effect, and are investigating the potential underlying causes, and whether the analyzed Follistatin gene therapy was a healthy or a disease-specific cohort, which has a huge impact in interpreting this result.Minicircle, the company that provided my Follistatin gene therapy, had shared their data in a pre-print in which their Follistatin gene therapy did not associate with a change in PACE, however still showed that it mildly reduced Extrinsic Epigenetic Age, with a strong correlation to T and B immune cells.(6)Tracking my epigenetic biological ageI continuously trace my epigenetic biological age using the PACE (DunedinPACE) clock, as discussed this clock is superior in both reliability and sensitivity, especially in detecting shifts in biological age in healthy cohorts, all desirable features for a biological age clock.It's worth noting: as far as I know, I am the most epigenetic-measured person in the world. We saw its potential early on as an important way to measure biological age and inform our decision making. We remain bullish.Results validate some longevity interventions, but mostly indicate a wide gap in the systemic understanding of other interventions and the reliability of "single aging clock approaches" and animal data in assessing longevity outcomes in humans.Metformin has long been of interest as a longevity drug, and while some mouse studies including ITP failed to demonstrate conclusive lifespan extension with metformin, the picture here looks much brighter, with 5 out of the 16 clocks indicating significant reduction/deceleration in biological age, with no clock indicating the contrary. A recent study on monkeys also used multiple aging clocks to demonstrate the anti-aging effects of metformin (4), particularly in the brain, here's my post on this study.Anti-TNF therapies also reduced biological age across most clocks, indicating the significance of "inflammaging" in driving the aging process.On the other hand, Rapamycin, which is consistently the strongest drug intervention at extending lifespan in mice (solo and in combination with other interventions) according to several gold-standard ITP studies, surprisingly drives an increase in biological age according to 2 of the clocks, while having no effect on the remaining ones. This further puts to question the validity of rodent data in predicting longevity interventions in humans.As for the vitamin-B rich Buckwheat extract, B vitamins drive the methylation cycle, which drives up wide genome methylation as seen in this large elderly cohort study (7), potentially accelerating the aging-associated epigenetic changes. Furthermore, long-term B9 supplementation increased cancer incidence and all cause mortality, with the effect specifically correlated to the folate concentration in the blood (8).Evaluation of Aging Clocks' Reliability and Sensitivity Shows the Potential of the DunedinPACE ClockBeyond validating interventions, the authors also assessed the reliability and sensitivity of the 16 tested aging clocks by comparing them to one another and gauging how often a clock's result agreed/disagreed with the majority of the remaining clock, as well as how often a clock was unique in detecting a different for a particular intervention.DunedinPACE clock (a next generation clock measuring the speed of aging) stands out here by being always either in agreement with a majority of the remaining clocks, or uniquely detecting a change in biological age, where no other clock did.Sensitivity of Aging Clocks in Health and Disease InterventionsFor the longevity field, aging clocks that can detect changes in biological age in healthy people are of particular value. Improvements from treating a disease are usually greater in magnitude and easier to detect than incremental improvements from longevity interventions in healthy people.True longevity interventions should drive biological age reduction in healthy cohorts too, as they address the underlying aging process as opposed to particular diseases.Three clocks showed significant effect detection in studies on healthy cohorts, including DunedinPACE, while also being significant in disease studies. The GrimAge clock, geared for predicting mortality, also showed efficiency in both contexts.7 Organ-System Clocks, and Proxy Epigenetic Markets of Metabolites and Proteins are Reliable in Predicting Intervention Effects, including Diets.The latest generation of epigenetic aging clocks is called Gen X (for generation explainable), they aim to make biological age assessments more understandable by focusing on specific epigenetic signature that can link the effects on systemic biological aging to specific organs (called Organ system Clocks) and/or biomarkers (Called DNAm Proxies), in a manner similar to how conventional studies seek to elicit the mechanism of a drug or intervention.The example below demonstrates how these epigenetic clocks can predict the effects of various diets on organs, systems, and biomarkers, in other words the epigenetic data reliably recapitulates what we know about the effects of these diets on organs and biomarkers (e.g. vegan and mediterranean diets reducing inflammation, low carb diet reducing HB1ac)Closing thoughtsAging clocks are mostly a proxy (surrogate endpoint) for the actual endpoint of interest, which is lifespan itself (mortality data). Relying solely on mortality data would delay the field by several decades.Since aging clocks were not specifically designed to independently predict the effects of of various therapies or interventions on aging, their accuracy in determining the effect of a particular therapy on epigenetic age is yet to be fully established as they sometimes isolate particular negative effects, while neglecting positive effects that can still be beneficial to extending life-and health-spans.This lack of reliability and accuracy motivated the development of several generations of aging clocks algorithms, and the resulting lack of consistency in implementing the various aging clocks is what motivated this study to create a roadmap for the optimal use of aging clocks to evaluate anti-aging therapies and interventions.Be well,BryanSources1. https://biorxiv.org/content/10.1101/2024.10.22.619522v1.full.pdf2. https://pubmed.ncbi.nlm.nih.gov/27312235/3. https://pmc.ncbi.nlm.nih.gov/articles/PMC6826125/4. https://pubmed.ncbi.nlm.nih.gov/39270656/5. https://bmj.com/content/330/7503/1304.long6. https://minicircle.io/wp-content/uploads/2024/04/fstpreprint.pdf 7. https://jamanetwork.com/journals/jama/fullarticle/184898
