A mitochondrially mediated mechanism for cellular senescence

 

A mitochondrially mediated mechanism for cellular senescence and apoptosis.

Fifty years ago in my PhD thesis on the aging  of rat liver mitochondria I described and produced electron micrographs of a population of mega-mitochondria within the liver cells of senescent rats. This population was also evident when isolated from ultra-centrifuge results using density gradientsto separate sub populations of mitochondria. Other work showed that mitochondria from the liver cells of senescent rats were more susceptible to osmotic shock than their younger counterparts and showed higher State 4 respiration rates.

I speculated then that mega-mitochondria with their evident lack of cristae had a smaller total surface area of the inner membrane leading to a smaller overall electrical capacitance. I coupled this idea with the facts that: mitochondrial membranes become more fragile with age and showed a greater State 4 respiration indicating a degree of uncoupled respiration.

I attributed significance to the idea of lower mitochondrial electrical capacitance, in that a smaller capacitance would need less charge, in a given time, to reach a threshold trans-membrane potential sufficient to provide the free energy to synthesise ATP. 

A 'leaking' membrane ( charge leakage) that struggled to build sufficient charge in a unit of time would appreciate a smaller capacitance simply to get to the point hat it could generate power.

Fifty years on I think that the above observations provide the basis for a mechanism of mitochondrial intracellular aging.

It can be expressed quite simply:

1) Electrons and protons, as raw materials for charge separation across the inner membrane, are supplied by food substrates in the normal metabolic pathways (as memorised by all undergraduate biochemists). The electrochemical gradient created by charge separation is then 'harvested' using the conventional chemiosmotic paradigm in order to drive the reaction of ADP towards ATP. 

2) There is a threshold voltage across the inner membrane, above which its potential energy can be transduced from electrical to chemical in the form of ATP and below which it can't.

3) The rate at which chemical energy can be drawn off the electrical potential depends on the rate of supply of charge to the membrane less any leakage of charge across the membrane; ie a dynamic 'net-potential' over time.That is to say not just the energy but the 'power' of a mitochondrion.

4) The supply of energy for ATP is buffered,  or smoothed out,  by the capacitance of the mitochondrion's inner membrane in order to givea constant supply ( say during fasting, or cell division ) to the cell.

5) The mitochondria's inner membrane's ability to do work ( ie supply chemical energy to the cell) is reduced by leakage of charge.

6) Charge leakage makes it more difficult to reach the threshold potential, ie it takes longer, and one way of mitigating this is to reduce the capacitance of the mitochondrial membrane ( fewer charges needed ) which in turn reduces the power output of the mitochondrion.

7) Excessive charge leakage leads to depolarisation of the membrane and potentially triggering apoptosis.

My hypothesis is that the aging mitochondrion is characterised by increased membrane leakage and reduced capacitance. Further,I speculate that the leaking, or uncoupling as it is known, is the result of endogenous substances. These uncoupling agents are to me potentailly the source of the mysterious aging clock that ticks within cells.

 It is known that leakier mitochondria can be replaced by more tightly coupled mitochondria for instance when a bat moves from a non-flying juvenile to flying adult. I can imagine a molecular uncoupling mechanism linked to a lifespan clock.

 It will be reversible!

Ozempic and Mounjaro: performance enhancers

 

Ozempic and Mounjaro

A lot has and will be written about the injectable near magical peptides that are bringing about profound

weight loss. These peptides go under brand names Ozempic, Weegovy and Mounjaro and the first two brands

may be known by their diabetic-clinic name ‘ semaglutide’.

Such peptides (including the simplest, insulin which is natural but also the first to be lab synthesised)  are involved in complex hormone-like signaling pathways affecting the way the body handles the glucose levels in the blood and its passage into cells. 

The synthetic peptides known as Ozempic/Weegovy and Montjaro when injected subcutaneously bring about weight loss. Sometimes this weight loss is a mixture of muscle and fat reduction, sometimes it is mostly fat. Muscle loss (known as sarcopenia) is undesirable but is also common in sedentary workers when dieting conventionally, especially with extreme calorie-restricted diets.

Fat loss without sarcopenia is a real achievement; the holy grail of dieters. Barring extreme carnivorous diets combined with extended endurance exercise and/or liposuction, fat, especially subcutaneous ( as opposed to intra-abdominal fat) fat is notoriously hard to shed. 

There is only one metabolic pathway to burn fat, and that is called  beta-oxidation. Beta-oxidation involves

fatty acids being fully oxidised  by mitochondriato carbon dioxide and water and thereby releasing energy in the form of ATP.

Actually, mitochondria don't directly metabolise or ‘eat’ sugar or fat, they ‘eat’ acetyl molecules. Acetyl molecules contain two carbon atoms as well as oxygen and hydrogen and are speedily delivered to mitochondria normally from the metabolism of glucose inside the cell.. If glucose is unavailable or energy demand is very high then acetyl can be obtained from fatty acids in a process called beta oxidation.

In a nut-shell ‘fat-jabs’ seem to enhance beta-oxidation and starve the mitochondria of sugar-derived acetyl.  Hence, fat is burned. If, unfortunately, some muscle cells,  laid fallow for many years as a result of a sedentary lifestyle, experience the sudden loss of glucose it is likely they will be killed off by the mitochondria in a process called cellular apoptosis.

Once the injections stop there is nothing to prevent the move back to ‘normal’ sugar metabolism via glycolysis and consequently the replenishment of fat reserves in the now empty ( but still there and alive) fat cells contained within shrivelled adipose tissue.

In conclusion, although I am sure that at the whole organism level there will be a plethora of exotic side effects it looks like these jabs are basically a ‘good fat burning thing’. They may well be  performance enhancing in endurance sports in which case they will be banned by WADA.

How you make a pill version though to get a peptide into the blood stream via the digestive system will be a trick I will be amazed to see …fat membrane droplets? Nasal spray?

Mushroom Powder and Cholesterol

 

Mushroom Powder and Cholesterol

Apparently mushroom powder as a dietary supplement is trendy. So trendy that Marks and Spencer, bastion of ‘mainstream but in touch’ now have their own range of products containing mushroom powder. ! Low fat, high in protein and fibre, mushroom powder products tick all the boxes, especially when made into a popular format such as ‘creamy shakes’.

When you search for the nutritional benefits of mushroom powders you get all the normal superfood guff but omitted is a very significant ingredient. That ingredient is called ergosterol. Ergosterol is a cholestero-genic compound, in other words it is a precursor to cholesterol. 

Like cholesterol It is readily converted to Vitamin D2 (via cholesterol) by the action of UV in sunlight, hence the availability of ‘Vitamin D enriched mushrooms’ which are pre-exposed to sunlight before sale. Another, closely related, cholestero-geneic compound is squalene found in extra-virgin olive oil. 

I just find it amusing that still living in a world that obsesses about levels of cholesterol circulating in the blood that two superfoods are exemplars of foods that increase blood cholesterol. This effect would be marvelous at increasing our Vitamin D levels if only we went out into the sunlight without factor 50 suncream to prevent it.

Oh well, it looks like cholestero-geneic diets are good for you, maybe even essential if you are on statins which stop your body making cholesterol.

ps..if you are interested, M&S mushroom products use 'Lion's Mane' mushroom powder which is particularly high in ergosterol.

UPFs gave me wagu thighs

Interesting article reproduced this week in the Financial Times from the annual meeting of the Radiological Society of North America held in Chicago. 

One group reported to the conference that in a study of 60 yr olds, whose diet consisted of approximately 40% so called UPF, but who did not consume excessive calories had ‘fatty thighs’!

They  differentiated between fat outside muscle tissue and fat within muscle tissue. In other words fat pads under the skin making the thigh look ‘fat’ and fat within the tissue itself. To those who eat meat, intramuscular fat is recognised and valued as ‘marbling’ because it enhances both taste, succulence and texture.

No hypotheses were put forward but one more nail in the UPF coffin was hammered home and it drew the usual scoff from the food industry who know that as a collective term UPFs are impossible to define…so are UPFs the bad guys here?

As a biochemist I wondered how quickly an hypothesis could be generated and how well it could be pinned to a modern UPFish diet or not..The answer was .. about 10 minutes.

The beef industry values marbling in meat the ultimate expression being in asian cattle and Wagu steaks. The adipocytes ( fat cells) within muscle are different to those outside tissue and respond to different signals most of which are poorly understood or studied. However mild injury and inflammation increases intramuscular adipocyte activity and fat infiltration in to the tissue. Some cattle are genetically disposed to intramuscular fat infiltration but other than the above the only strategy to increase marbling is to add conjugated linoleic acid to the feed. These are called CLAs and can be synthesised as well as being present in natural foods.

Natural sources of CLAs are basically: milk, cheese and meat.. The highest values I found published when a quick web search was carried out are in milk, ground beef and mozzarella cheese.

So, let me think: latte coffees, burgers and pizzas should max out our CLA intake

There you go, nothing to do with bad stuff in the foods, after all you can get the highest quality of unadulterated ingredients in all three of the foods above, but if you have a latte each day, burgers twice a week and a take away pizza, you’ll probably get wagyu-thighs!

Ps if you are wondering what the intramuscular fat is doing in your muscles, quite simply it is an energy store placed as close as possible to the muscle mitochondria which use fatty acids as slow burn fuel. Ideal for a labourer maybe not ideal for an office worker.

Senescence: time for humanity to enter the dying phase

 Time to start dying.

I have just re-read the opening paragraph to my 1979 Ph.D thesis on the Biochemistry of Ageing (Rat Mitochondria). It laid out the goal of the field of study called gerontology. In a nutshell, the goal was: ‘the extension of years of active life before entering the senescent phase’. It also said explicitly that increased life span due to prolongation of the senescent phase was a bad idea, something I feel with which few would disagree.

Unfortunately I think in the last fifty years we have achieved mostly  the latter and in the worst way. There has been an increase in UK average maximum life span ( about 3 years more for men and women) in that time but I am increasingly thinking that the senescent phase is starting earlier. 

In the UK the cost to the taxpayer of supporting the long term sick is large, increasing and unsustainable. I think a great many of this group have entered a  senescent phase, or at least a version of it. This assertion needs a lot of unpacking to sound credible.

Firstly we expect old people to look old. We readily recognise superficial phenotypes denoting ‘old’;  low energy, wrinkles, faltering gait, muscle loss, incontinence and bone fragility to name a few. Some of these such are products of deteriorating connective tissue which is a time-dependent passive chemical process rather than a reflection of physiological or biochemical ageing. Physiological changes, say to do with muscles or the brain on the other hand are under active processes. Processes we now know are ultimately mediated by mitochondria via internal and external signals

Now, the broad signals  for a cell or a body to enter a senescent phase are well known. They are DNA damage ( eg from radiation, pollution,toxins) , epigenetic ( eg onco-viral),  telomere erosion ( the ability for a cell to divide) and mitochondrial dysfunction. All except telomere erosion can be influenced by environment, diet and lifestyle.

To follow the argument in this post you need to imagine a senescent individual who does not look old. So his/her limbs and body will remain plump, skin smooth-ish, and heads hairy. They will however also be largely inactive ( low energy) and suffering from chronic inflammatory diseases like arthritis and IBS and dementia. Low immune surveillance will also lead to an increase in early onset cancers especially where inflammation is high, eg the gut. Sarcopena ( muscle loss ) will also be evident, though largely hidden by intramuscular fat. Finally, mental health issues such as depression and anxiety come to dominate cognitive processes.. In all respects characteristics of folk in teh senescent phase.

How could this happen? How did the ‘not-old’ enter a senescent phase? ‘Signals’ are received and acted upon by an organism on very many levels. For example mitochondria ‘note’ energetic demands, the amount and character of ‘food’ being delivered, the level of damage in the cell, the activity of endogenous and exogenous viruses, exposure to NIR light at dawn and dusk. The list goes on, and mitochondria proliferate or die or kill the whole cell depending on what they find.

At a more complex  level the mind responds with behavior changes according to the perception of the environment, broadly divided into good times or bad times. Bad times triggers reduction in mating and vice versa. 

As you can see in the profile of the Ist World human there are plenty of candidates to signal ‘it’s all over chums go into senescence’ .  And with very bad luck modern medicine will prolong this phase even longer. Happy days.

Dementia, shingles and statins ...pharma's biggest oops!

I have just returned from my local GP surgery for a routine check and saw a poster informing all that one

in four adults will get shingles. Excuse me! One in four? I would have queried this figure except

for the fact that amongst my 60+ peers I find shingles is, well, rampant.. and consequently

I am looking for my free shingles vaccination as soon as I turn 70.

Shingles is nasty, painful and infectious; especially to those who never had chickenpox or the chickenpox vaccination. Worse, you are not guaranteed to get better. Shingles is a bit like its relative the herpes cold sore, it is a reactivated virus acquired earlier in life. Shingles is a reactivated chickenpox virus once living quietly in nerve cells.

How is it reactivated?  The consensus is that it is a result of an immunosuppressant failure. Duh! This is restating the obvious and has no information associated with it other than some very interesting data.  Patients medicated with statins have an increased susceptibility to shingles. I am not joking.

Studies show that people who take cholesterol-lowering statin drugs are at higher risk for developing shingles. “A possible reason,” says Dr. Cohen, “is that statins may affect the immune system.”  For further info confirming this:

https://bmjopen.bmj.com/content/9/2/e022897

A wide range of viruses ranging from Herpes to Covid to  oncoviruses ( cancer causing) typically target mitochondria once they have gained entry to a cell. The reason is simple, mitochondria control cell death ( apoptosis ) and will cause the cell to commit suicide in response to infection.

Shutting down the cell, the apoptotic response to something going wrong within a cell, is an integral part of the basic immune response to infection (and indeed of the termination of cancerous cell too).

Mitochondrial morphological changes occur as virus Herpes Zoster virus reactivation progresses showing that front line defence against reactivation is being compromised.

So, readers of my posts will be already aware of what comes next:

Statin medication affects mitochondrial health through alteration of cholesterol availability. Lowered mitochondrial health sometimes  leads to apoptosis of muscle cells in some individuals ( muscle pain, sarcopenia) and in others or even the same people  lower immune surveillance of endogenous viruses such as herpes zoster, ie they get shingles.

One in four should expect to get shingles!. What are the figures for those over 60 on statins? A tsunami of statin related health outcomes are coming our way

post script: 

I have just had my shingles vaccination (the recombinant vaccine not the live vaccine) and I am v happy with this especially when a little more research informs me that the vaccine helps protect against dementia. Another 'what!!'  It seems like it does not matter if it's the live or recombinant vaccine, both work. But why? No mechanisms are proposed. 

I have a mechanism. Shingles are linked to statin use. My proposition is that the nerve cells invaded by the resurging Herpes Zoster virus are made disproportionally vulnerable by statin use ( unsuprising maybe given how much cholestrol is needed in the myelinated axon's insulation sheath)  So in the shingles v dementia findings it is simpler to see shingles as a vulnerability sympton rather than a cause of nerve deterioation. Yes, the net is closing in around statins' unforseen consequences.

We, Gen AZ are different.

  

Do you find nowadays that you ‘start a cold’ or go to bed feeling that ‘something is coming' on’ fully expecting a minor illness only to wake up with it gone? Can you remember the last time you went to bed with a bug? If not you are probably a member of Gen AZ.

‘Boomers’ plus Gens X, Y,  Z  and now A, are shorthand labels that conveniently divide the spread of population ages into chunks that facilitate ‘targeted messaging’. The letters replace terms such as  ‘old’, ‘middle aged’, young, adolescent and child which enables ‘market targeting’ to sound a bit more academic than it is really.

This post is about a very different generation..Gen AZ. Gen AZ is anyone old enough to be vaccinated against Covid 19 in the early 2020s who received the adeno-virus vaccine delivery vector designed to produce the now famous ‘spike-protein’ which in turn primed the immune system in order to fight the then deadly Covid-19 virus 

Sounds complicated? Yes indeed, it’s sufficiently esoteric to be utterly incomprehensible to non-biochemists. However incomprehensibility does not mean insignificant. Known colloquially as the ‘Oxford-vaccine’ and manufactured by Astra-Zenica only a relatively few people globally can lay claim to be GenAZ. Gen AZ  has indeed received the ultimate in ‘targeted messaging’. 

Back in the day, as they say, when Covid 19 was rampant and the race for mass, global vaccination was on, only three pharma companies understood the RNA recombinant technology and had the expertise to safely, in quantity, make an effective  Covid 19 vaccine. These were Astra-Zenica, Pfizer and Moderna. Many companies around the globe  could not do this. In Russia, China, India and Europe there were famous mega-pharma companies who simply could not master the technology. 

Of the effective new vaccines there were two types. The so-called mRNA vaccines made by Pfizer and Moderna and the Adeno-virus DNA vector made by Astra Zenica . Given the vast scale of the vaccination programmes both technologies proved to be remarkably safe as well as amazingly effective. However AZ vaccinations which dominated the initial program in the UK were soon superseded in subsequent immunization programs by either Pfzer or Moderna. For example in my own instance, as a boomer gen member in the UK, I got my first two early jabs from AZ. Subsequently I have had only Pfizer and Moderna. Friends in nearby Ireland, slightly late to the party, never got the AZ vaccination at all. AZ quietly disappeared following ‘bad reaction scares’ which in hindsight were not significant.

We, Gen AZ are different. 

Some readers may remember trolling memes emanating from Russia at the beginning of the pandemic when the announcements that the vaccines were coming brought relief and hope to millions. Crudely put the vaccines, they said, would modify our DNA and turn us into apes or something. Vaccine fear was born ‘bigly’ as the USA president at the time may have said. Even though simian traits have been displayed by many of our leaders this prophecy has needless to say not come to pass. But the trolls were right in an important way.

After Astra Zenica bowed out leaving the field to Pfizer and Moderna they moved a development  lab from their UK base to Ireland. Shortly after that, a paper from the Basedo lab at Trinity Dublin1, was published showing ‘non-target’ immunity from Gen AZ. In other words some generalized immunity to infection seemed to persist in those who had had AZ vaccine. Cue, end of trail.

Introducing attenuated and genetically modified ( ie it is engineered so that it can't reproduce) adenovirus DNA into a cell is wholly different to introducing mRNA. mRNA has a short shelf life before it is broken down and its components recycled. The fate of introduced DNA is far less certain. 

Introduced DNA may be broken down in the cell, or it may not; it may persist as free epigenetic DNA, it may be incorporated into nuclear or mitochondrial DNA; it may be repaired; it may be transcribed fully or in part to make mRNA and thence proteins identical to to alike to the ‘spike protein’. So logically it is overwhelmingly likely that Gen AZ has modified DNA.

What does this mean? Firstly I think this is the first and last time the Adenovirus vector is used en-masse and secondly Gen AV is being followed very closely. What fate is in store for chimeric Gen AZers? We’ll see.

1. https://www.irishtimes.com/health/2023/01/18/covid-wider-benefits-to-astrazeneca-vaccine-trinity-research-indicates/

https://www.tcd.ie/news_events/articles/2023/research-indicates-wider-benefits-to-astrazeneca-vaccine/

For a clear description of the methods of vaccine delivery into cells the article below from Nature is worth reading.

https://www.nature.com/articles/s41541-021-00356-x