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.