John Hemming's Web Log

In Parkinson’s disease, dopaminergic neurons (primarily those in the substantia nigra pars compacta) undergo progressive dysfunction and death. In amyotrophic lateral sclerosis (ALS aka MND in the UK), both upper and lower motor neurons progressively degenerate. The cells deteriorate in different ways. However, the nub of both of theses diseases is the deterioration of a particular type of neuron. An interesting question is what it is about these neurons that makes them vulnerable to rapid deterioration. Neurons are high energy cells. Dopaminergic neurons have to maintain a massive network of axons linking them to other cells. Similarly motor neurons need to maintain long axons of possibly 1 metre in length. All of this takes energy. However, what distinguishes these two types of cells is that they rely to a greater extent on Oxidative Phosphorylation (that is using the Krebs cycle to produce energy) than other neurons. OxPhos, has the effect of generating more free radical...

ALS (Amyotrophic Lateral Sclerosis) tends to be called MND (Motor Neuron Disease) in the UK. It is also known as Lou Gehrig's disease because he was a famous baseball player whose career was ended when he died of ALS in his 30s. There are perhaps two main versions of ALS Familial (or inherited) and Sporadic which does not appear to be inherited. MND is perhaps a broader category which includes Progressive Muscular Atrophy (PMA), Primary Lateral Sclerosis (PLS) and Progressive Bulbar Palsy (PBP) as well as ALS. In this post I am going to concentrate on ALS. That is not to say that things I say in this post do not necessarily also apply to the other types of MND, but I have not looked at that question as yet. I wrote a post a few weeks ago What causes Parkinson's Disease - is it actually an accelerated form of brain aging? and since then have been doing some experimentation with a small number of biohackers who have Parkinsons Disease. The hypothesis is basically that th...

An interesting paper was published recently. Intracellular metabolic gradients dictate dependence on exogenous pyruvate This was from the same lab as the excellent paper A non-canonical tricarboxylic acid cycle underlies cellular identity . An interesting question that the paper answers is what drives the need for external pyruvate. The paper concludes "The requirement for pyruvate over lactate can be partially rescued by NAD+, suggesting that at least part of the role of pyruvate in development is regulation of cellular redox62. ". What I find particularly interesting about the link to NAD+ is that Complex 1 (which is reduced in stem cells) has a major role in maintaining NAD+ levels. Hence if it is to be inhibited in some form then something else needs to be done to maintain NAD+ levels. Although Complex 1 maintains mitochondrial NAD+ rather than cytosolic NAD+, depletion in the Mitochondria will block the Malate-Aspartate shuttle affecting the cytosol Pyruvate in th...

Recently another paper was produced which hinted at a link between mitochondrial DNA damage and aging. In fact I have been of the view for some time that the damage to mitochondrial DNA is what drives both aging and development at the lowest level. I have said this before, but thought a summary would be useful. It is worth, however, explaining a few terms first before going into the details of how this happens. It is well known that animals (including people) are made of large number of cells. Within those cells there are little "organelles" called mitochondria that are used to convert nutrients into ATP (Adenosine Tri Phosphate) which is used by cells as a form of energy. There is a hypothesis that is generally believed to be true that this structure of cells arose from some bacteria going into old cells called archea as it created a form of symbiosis where the larger cells provided nutrients to the bacteria for the bacteria to process those. This is called Endosymbio...

The idea that Parkinson's Disease (PD) is an accelerated form of brain aging has been around for quite a long time. However, as with aging more generally any hypothesis as to the mechanisms behind Parkinson's needs to explain all the known research data. I have been discussing PD with a number of people over the past few months. The results from research indicate that Parkinsons is not primarily caused by genetic factors. That is because there are studies where individual twins get Parkinsons, whilst their twin does not. I was wondering, therefore, what might be an alternative cause. This paper is one that substantiates the argument that normally the brain does not age as fast as the rest of the body. What we need to look at is what might cause this to happen. If we start with the assumption from my previous posts that aging results from the mutation of mitochondrial DNA (mtDNA) then we need to find something that prevents the mutation of mtDNA in the brain that does n...

Software Developer and Artifical Intelligence Expert Samuel Collingwood Smith has been working with me on a number of projects for a last few years, mostly in the Artificial Intelligence / AI / bio-hacking space. We entered a number of competitions, some of which were against billion dollar organisations and in one case came in the top-ten with software that runs on a desktop PC, on an nVidia card, against thirty other competitors. As well as using open source AI models hosted in Python, Smith has used his C# and C++ tools to develop his own scratch-written neural network engine, LearnSilver. This is a C# native neural network library that can also execute on CUDA enabled nVidia cards with C/C++, including many gaming graphics cards. It enable significant processing on consumer hardware. It supports training, serialisation of entire models with a single method call and recurrent networks. TALIS is a side, personal project Smith worked on prior to joining me in setting up our new AI c...

The Biohacking Team has withdrawn from XPRIZE Healthspan. We think the prize is a really good idea and the science behind the judging is really good. However, we are not willing to sign the competitors agreement. XPRIZE have asked that the competitors agreement be kept confidential and hence we should not give our reasons as to why we will not sign the competitors agreement. Signing the competitors agreement is a requirement for remaining in the contest, hence we need to withdraw. We wish XPRIZE Healthspan well. Finding out what can be done to increase the proportion of people's lives in good health is a really good idea. We have, however, decided to keep the team together. Although the team was brought together to compete in XPRIZE and we are no longer doing that, we have other things to do. We have already participated in the Biomarkers of Aging contest and the Medical Affairs Olympics. We are also running small scale biohacking coaching sessions on both the Diseases of ...

The Electron Transport Chain has five complexes. These are comprised of a number of subunits. What I find particularly interesting is that some of the proteins are generated via nuclear DNA and some of the proteins are generated via mitochondrial DNA. Most of the ROS (that damages mtDNA) is generated by Complexes 1 and 3. Complex 1 has 45 subunits in humans, but in fact only 7 of those (ND1, ND2, ND3, ND4, ND4L, ND5, ND6) are encoded by the mitochondrial genome. Complex 3, however, has 11 subunits only 1 of which is in mtDNA (MT-CYB) Complex 2 is entirely coded by the nucleus, Complex 4 has 3 (MT-CO1, MT-CO2, and MT-CO3) out of 13 units coded in mtDNA. ATP Synthase also called Complex 5 has 16 units two of which are encoded in the mitochondria. Hence it is clear that complex 1 is perhaps the key complex for mtDNA mutation linked aging and not surprising that this is the complex inhibited in Oocytes. There is an argument that for hydrophobic subunits the energy cost of transferr...

Oxygen is essential for human life. That is well known. However, the level of Oxygen in the atmosphere has interesting effects. I wrote previously about The Hypoxia Inducible Factor (HIF). HIF (particularly 1 alpha) is a molecule which signals cells to create proteins to build in response to stress. This can involve building new mitochondria or recycling old inefficient mitochondria. In essence it is ringing an alarm that calls for cells to get better prepared for stress. Interestingly HIF is switched on by a drop in the oxygen partial pressure (that proportion of air pressure that is oxygen). It is also well known that if brain cells get too little Oxygen then they can get harmed or die. Hence too low an Oxygen level causes brain damage. In fact there is evidence from people living at high altitudes that at a point the oxygen level is too low and this harms health. However, there is another aspect of Oxygen levels that relates to the mitochondria. The mitochondria produc...

There are a number of theoretical debates about aging. One is the question of whether we are "programmed to die". Those who believe this think that at a point creatures get to a stage where the organism at a cellular level starts processes which deliberately set out to end the life of the multicellular organism. Another potentially contradictory view is simply that creatures accumulate damage up the point at which they can no longer survive. It is possible, however, to look at different species and see how their lifespan operates. What is clear is that different species age in different ways. Some species don't age in the same way as others. It is worth having a look at how species vary and to what extent that explains the relationship between evolution and lifespan. Firstly, it is clear that there are species where the adult commits some form of suicide after mating. Octopuses and Pacific Salmon There are, however, also species which have negligible senes...

An interesting paper was published in the week before Christmas. Mitochondrial quality control: the real dawn of intervertebral disc degeneration? The summary states: Intervertebral disc degeneration is the most common disease in chronic musculoskeletal diseases and the main cause of low back pain, which seriously endangers social health level and increases people’s economic burden. Disc degeneration is characterized by NP cell apoptosis, extracellular matrix degradation and disc structure changes. It progresses with age and under the influence of mechanical overload, oxidative stress and genetics. Mitochondria are not only the energy factories of cells, but also participate in a variety of cellular functions such as calcium homeostasis, regulation of cell proliferation, and control of apoptosis. The mitochondrial quality control system involves many mechanisms such as mitochondrial gene regulation, mitochondrial protein import, mitophagy, and mitochondrial dynamics. A large numbe...

The fact that mitochondria have their own DNA has been known for a number of decades. However, reading that DNA is harder than the nuclear DNA. That is because there are multiple copies of the DNA in individual mitochondria as well as there being more than one mitochondrion in most cells. However, science has now developed techniques for analysing the mitochondrial DNA in quite subtle detail. In 2024 a number of interesting papers were produced which I will talk about in this post The rate and nature of mitochondrial DNA mutations in human pedigrees is paper produced by a number of researchers in Iceland. The abstract states: We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position...

I have seen a surprisingly upbeat post from Sonia Poulton about Sam Smith’s appeal against her. In fact, like so much of what she says, she is misleading her followers. To explain briefly, earlier this year Sam and I applied to strike out parts of Sonia’s case in the ongoing lawsuit between Sonia on one side, myself Sam and Darren Laverty on the other. Sam helped with both applications along with two barristers. They were heard on 1 May 2024. The first application won - part of Sonia’s case was struck out as inconsistent with an earlier witness statement. Some would call that, “lies”. Sonia did not appeal. The rest of the strike-outs failed. After taking advice from counsel, Sam appealed and got permission from Mrs Justice Steyn DBE. The appeal failed, except that the judge ordered Sonia to clarify her case in a formal statement called a Part 18 Response. In effect, she abandoned 11 of the 21 pleadings we were trying to strike out, promising not to rely on them or file evidence on t...

Biohacking to Improve Everyone's Health, the team of Biohackers intending to compete in XPRIZE Healthspan, have reached the top ten in prediction of mortality using methylation data in the second round of the Biomarkers of Aging competition. The contest aims to use data on methylation of DNA sites and other biomarkers to determine the biological age of individuals and predict outcomes such as mortality. The Biohacking team, including software developer and machine learning expert Samuel Collingwood Smith, used their own proprietary software called LearnSilver to develop their prediction models, in combination with other tools. LearnSilver is a .NET C# / C++ / CUDA software library that allows execution of complex neural networks, including recurrent networks, on consumer hardware along with efficient serialisation. The library can execute in single-threaded mode on a CPU, or multi-threaded mode and it can also leverage nVidia hardware for massively parallel operations. Sam Smit...

Biohacking to Improve Everyone's Health , the team of Biohackers intending to compete in XPRIZE Healthspan, have won some early prizes in the 2024 MEDICAL AFFAIRS INNOVATION OLYMPICS #MAIO2024 . The MAIO is organised by The Medical Affairs Professional Society and sponsored by a number of leading biotech companies including Amadea Pharma . Of all of the biotech groups proposing ideas the Biohacking Team won the "high jump" the prize for the most lofty idea. The team also got the overall bronze award in Patient Centricity. John Hemming, leader of the Biohacking Team said, "I am pleased that the MAIO recognised our proposal for improving gene expression as being the most 'idealistic, lofty concept with a vision' of the varied ideas being presented at the contest. Our challenge, of course, is to refine the proposal and demonstrate that it broadly has beneficial effects in extending healthspan." These are the main two presentations at the MAIO 202...

When it comes to development there are a number of steps which can be quite well defined. One, of course, is death. Another is birth. Then there is sexual maturity and for some people menopause. There are plenty of papers which link precocious puberty with early menopause. There are also those which link early menopause with higher mortality and earlier age based diseases. This points to those being driven by the mRNA splicing changes and other changes in mRNA transcription primarily from the average mitochondrial membrane potential. I was wondering recently, however, about birth. Is that step potentially driven by MMP. There are a number of pieces of evidence that point to this. One is that mothers who were born prematurely are also likely to have premature children. Importantly people who are born prematurely also face health problems in their lives at an earlier stage. An overview of adult health outcomes after preterm birth " Large cohort studies have shown that ...

I recently attended the British Society for Research on Aging annual scientific conference which was held this year in Birmingham. There were a number of interesting talks and about 45 posters were presented. This included one from me. The details in that poster can be seen on this link . One benefit of conferences which are in person is that conversations can continue after the presentations and issues can be refined through discussions either in the corridors or over food. The area I am particularly interested in is how the links between mitochondrial efficiency and the genome operate. I managed to refine my understanding of two of the aspects here. The Citric Acid Bicycle The first area I managed to refine is to understand the mechanisms that underpin citrate efflux from the mitochondria. To understand this fully it is perhaps best to consider the operation of two citric acid cycles. In fact realistically it is a Citric Acid Bicycle - as the two cycles are linked. Th...