This is the summary from Zoom
Quick recap
John presented a lecture on aging from an evolutionary perspective, discussing how different species cope with environmental niches through various developmental and lifespan strategies. He shared his personal biohacking experiences and research findings on acetylation processes, mitochondrial function, and the role of transcription factors in aging. The discussion covered detailed mechanisms of mitochondrial DNA, acetylation pathways, and various interventions that could potentially slow aging, with the group agreeing to continue the conversation in future meetings.
Summary
Evolutionary Perspectives on Aging
John presented a lecture on aging, discussing whether aging is intentional from an evolutionary perspective or an error, and the importance of acetylation as a post-translational modification. He used examples from various species, including bees, bats, and fish, to illustrate how evolution can set lifespan and development styles to cope with specific environmental niches. John also touched on the concept of negligible senescence in some species and the possibility of reversing development in certain cases, suggesting that evolution has established a program that can be influenced.
Biohacking and Mitochondrial Efficiency
John discussed his biohacking experiments and personal observations, including the reversal of preclinical cataracts, which he attributed to improvements in mitochondrial efficiency. He proposed that acetylation of histones and subsequent gene expression are linked to the efficiency of mitochondria, which he views as a key factor in controlling the aging phenotype. Walter raised a question about the complexity of histone modifications beyond acetylation and methylation, noting that many other modifications are not well studied due to measurement challenges. John emphasized the value of in vivo testing for hypotheses related to aging and transcription factors like vitamin D, which he sees as regulating protein production in response to nutritional availability.
Mitochondrial Acetylation and Aging Mechanisms
John explained that the development clock is primarily driven by acetylation, which is influenced by both histone and DNA methylation, and is largely determined by the status of mitochondria. He discussed the diversity of mitochondrial DNA within the body and the role of senescent cells in aging, as they produce SASP which reduces acetylation through Janus kinase inhibitors. John also described the citric acid cycle and its non-canonical counterpart, emphasizing the importance of acetyl-CoA levels in driving acetylation and the role of the citrate carrier protein in exporting citrate from mitochondria, which is influenced by the proportion of iron in citrate.
Citrate Distribution and Metabolic Regulation
John explained the distribution of citrate species at different pH levels, noting that at the physiological pH of 7.4, about 20% of citrate is in the protonated form, while at the higher pH of the mitochondrial matrix (around 7.8), only about 6% is protonated. He discussed how the citrate carrier enzyme uses protonated citrate, while the next step in the Krebs cycle, Aconitase, uses the 3-minus form, allowing for the regulation of citrate flow in and out of the mitochondria. John also described how the acetylation of the ACLY enzyme affects its translocation to the nucleus, where it processes citrate for acetylation of proteins, suggesting that the level of acetylation could be an indicator of biological age or development age.
Mitochondrial Interventions and Aging Research
John presented a detailed overview of mitochondrial DNA, acetylation processes, and various interventions that can improve mitochondrial function and potentially slow aging. He discussed mechanisms such as reducing mitochondrial damage, the role of melatonin, antioxidants, and selective mitophagy. John emphasized the importance of understanding how different interventions can work synergistically or antagonistically and highlighted the need for further research and debate on these topics. The group agreed to continue the discussion in future meetings and to review the presentation materials provided.