John Hemming's Web Log

In Aubrey de Grey's 2015 Paper Do we have genes that exist to hasten aging? New data, new arguments, but the answer is still no he puts forward a number of arguments as to why he believes aging to be other than programmed aging (PA). One of these argument is his "COA Cancelling out argument". I extract from the paper his reasons for this. STRONGER CHALLENGES TO PA A simple but remarkably rarely stated argument against PA, which here I shall term the “cancelling-out argument” (COA), is that it is impossible for a species to maintain two sets of genetic pathways whose selected actions diametri cally oppose each other. Specifically, since we clearly have a large amount of genetic anti-aging machinery (repairing and pre-empting the damaging side-effects of metabolism), we cannot also have pro-aging machinery that accelerates the accumulation of such damage, unless the latter machinery is selected for another purpose. The logic leading to this con clusion is ...

As I biohacker I do quite a bit of self-experimentation. There is an interesting ethical question about self-experimentation. Obviously people have the right to make their own decisions. Self Experimentation has a long history in Medicine and at least five Nobel Prize winners have won a prize following self experimentation. However, it is potentially dangerous and people have died. The ethical question is whether researchers should be penalised by being unwilling to self-experiment. To that extent some US ethics committee argue against the academic publishing system accepting the results of self-experimentation. I personally, unsurprisingly, think that is wrong. There should not be a condition of employment that people self-experiment, but it cannot be right to exclude the results. We also need to recognise that there are serious problems with animal experiments. Everything Wrong with Mouse Studies (Kinda) subtitled: Odors, magnetic fields, and even a mouse's siblin...

Professor Thomas Seyfried and the Question: Is Cancer Primarily Nuclear DNA or Mitochondrial DNA? Professor Thomas Seyfried argues that cancer is mainly mitochondrial rather than purely nuclear/genetic. Below are the key experiments supporting the view that cytoplasmic/mitochondrial factors, rather than nuclear mutations alone, drive the malignant phenotype. Nuclear Transfer Experiments (Cancer Nuclei → Normal Cytoplasm) McKinnell, R.G., Deggins, B.A., Labat, D.D. (1969) Transplantation of pluripotential nuclei from triploid frog tumors Science, 165(3891):394-6 Summary: Nuclei from frog renal tumor cells transplanted into enucleated eggs developed into normal swimming tadpoles, demonstrating that cancer nuclei retained developmental pluripotency when placed in normal cytoplasm. McKinnell, R.G. (1979) The pluripotential genome of the frog renal tumor cell as revealed by nuclear transplantation International Review of Cytology Supplemen...

Analysis: mRNA Splicing & Childhood Development This analysis evaluates the role of mRNA splicing in human childhood development, distinguishing between splicing as a primary driver of developmental milestones versus a secondary consequence or fine-tuning mechanism. Executive Summary The evidence indicates that mRNA splicing is a critical functional driver of specific developmental phases in childhood, particularly in brain maturation (synaptic plasticity) and musculoskeletal adaptation . While transcriptional changes (turning genes on/off) generally drive early fetal cell fate , alternative splicing takes over in the postnatal/childhood period to drive cellular maturation . Therefore, splicing is likely a primary driver of functional specialization . 1. The Case for Splicing as a Driver of Childhood Development In this context, "driving" means that the developmental change would not occur—or would occ...

Prompt: ""of the diseases of aging which are assocated with changes to RNA splicing" Diseases of Aging Associated with Changes to RNA Splicing Many major age-related diseases have documented links to altered RNA splicing—both via age-related drift in the spliceosome and via disease-specific mutations in splicing factors or cis-elements. Below are key examples by system (not exhaustive, but covering major, well-supported cases). 1. Neurodegenerative Diseases Alzheimer’s disease (AD) What’s altered? Alternative splicing of tau (MAPT) , shifting 3R/4R isoform balance. Splicing of APP , PSEN2 , and various synaptic genes. Mechanism: Mis-spliced tau isoforms are more aggregation-prone and disturb microtubules; age-related decline in spliceosome components (e.g. SRSF and hnRNP proteins) pushes splicing patterns in a pro-pathology direction. Frontotemporal dementia (FTD) and other tauopathies What’s altered? ...

I put a couple of prompts into Gemini and the following came out as answers: Impact of RNA Splicing on Endothelial Function in CVD User Query To what extent are protein changes as a result of RNA splicing changes that cause endothelial problems part of cardiovascular disease? AI Analysis Protein changes resulting from aberrant RNA splicing in endothelial cells are not merely bystanders but are increasingly recognized as active drivers of cardiovascular disease (CVD). To answer your question directly: these changes contribute to CVD to a significant extent by creating "molecular switches" that can flip a healthy endothelial cell into a diseased state without necessarily changing the total amount of the gene being expressed. This process often explains why a patient might have "normal" levels of a protein but impaired function. The following s...

The principal mitochondrial K+ uniport is associated with respiratory complex I is an interesting preprint that has been withdrawn "due to disagreement with UCSF over data rights. This withdrawal decision is not related to the validity of the data presented in this study, and these authors understand that this work cannot be cited as reference for the project until the disagreement is resolved." It remains, however, interesting. The reason I find it interesting is that there is clear evidence that there is a link between the delta pH between the mitochondrial matrix and Intermembrane Space and the mitochondrial membrane potential. This was evidenced in experiments which varied one and saw the proton motive force (which is the total of the two adjusted for the same units) remain essentially constant. Furthermore it seems that where Potassium Ion transport changes with age we can also see a reduction in the membrane potential, but an increase in delta pH. This is signif...