Capacitance Hypothesis for Mitochondrially Mediated Aging

Capacitance Hypothesis for Mitochondrial Mediated Aging.

The capacitance hypothesis can be summarised as follows:

Mitochondria are electronic devices analogous to electrolytic capacitors. 

As mitochondria age they become increasingly uncoupled ( ie they leak charge) most probably through the mediation of the uncoupling proteins (UCPs). Mild, partial, progressive uncoupling results in a decrease in maximum power, slower recharging (to the required threshold pre-discharge voltage) and a diminished energetic capacity. Full depolarisation results in apoptosis (cell death).

Genetically programmed uncoupling through UCP variations provides a simple basis for a mechanism for determining life span. 

Background: Mitochondria, acting at the cellular level are central both to the aging process and the final onset of senescence. Below are four (uncontroversial) statements supporting this assertion:

• Mitochondria produce free energy, in a chemical form, which is used to drive metabolism and this ‘energy’ decreases with age.1

• Supergeriatric humans (lifespans > 100) when compared to ‘normal’ humans (lifespans  <90) show no differences in nuclear DNA (nDNA)2in whole genome analysis but do show variations in mitochondrial DNA (mtDNA)3

• Mitochondria become progressively uncoupled ( electronically leaky) with age4,5,6: supergeriatrics v normal humans show age-related differences  in so called uncoupling proteins (UCP1-4) which regulate mitochondrial ‘leakiness’.7

• Animals with highly coupled mitochondria ( eg bats, pigeons) live proportionately longer lives than animals of equivalent size that do not ( eg bats v mice 20yrs v 2yrs)11

Fifty years ago my research12 was led by the first of the bullet points - we notice with ageing that we have less energy!. Since that time fifty years ago, technological developments have enabled genome sequencing and rapid structural analysis of proteins but has disappointingly yielded very little progress on the fundamental driving processes of aging. Telomer shortening and free-radical damage13 theories have come and gone in this time, but steadily little by little  the focus has shifted back towards the mitochondrion. So much so that as I write mitochondrial underperformance is being asserted as causal in Alzheimer' s brain deterioration14

Presented here are novel mechanisms for the gradual age-related changes in mitochondrial function, consistent with the facts above, and consistent with experiential changes of aging which are well known to all of us. Additionally, as a corollary, a mechanism for the variation in the life span of mammals is proposed based on a hypothetical determinant mediated by mitochondria.

Mitochondria as electrical devices:

Mitochondria have all of the characteristics of the free-living creatures; that is their biology, physiology, and biochemistry are complex and under the influence of the normal cellular processes from biosynthesis/destruction to reproduction and signalled controls.

I wish to focus here though on one neglected ( I think) aspect of their nature: electronics. This possibility, the electronic nature of mitochondria, came to be a possibility as soon as the transmembrane potential(  ie a voltage, symbol ΔΨ ) was recognised following Michell’s Chemiosmotic15 proton gradient theory over 60 years ago.( For this article protons (H+)  themselves somewhat mythical beasts, are treated  as anti-electrons, analogous to electron holes in the semiconductor world). To date, as far as I can read, the electrical engineers have not had much input into this field, which I hope to rectify (pardon the pun). As a result I am not differentiating in an electronically meaningful way between proton gradients and other ionic gradients. I am just interested in charge separation, electron rich and electron poor regions, or positive ion rich or positive ion pore, separated by a barrier with a known dielectric; it’s all the same.

In this document, mitochondria are regarded primarily as electrical devices, in that they use electrons ( via ion pump proxies) to generate membrane potentials (voltages) and have capacitance ( the ability to store charge) proportional to the surface area and dielectric of the inner mitochondrial membrane. The energy stored by these mini-capacitors is used, in batches, analogous to capacitor discharge, to liberate the Gibbs’ free energy which in turn is used to drive metabolic processes which require it ( for example the synthesis of ATP from ADP and Pi which requires by the way 73 joules of free energy.).

As with capacitors used in the world of electronics, the devices ( mitochondria in this case) have a time-based charging curve, a rapid discharge curve, a dielectric constant based on the lipid composition of the inner membrane, a total capacitance and a charge-leakage profile.

Diagrams:

The diagrams below show a mitochondrion charging through a supply of electrons from oxidisable substrates then rapidly discharging as a threshold inner membrane potential is reached sufficient to generate ATP ( or other phosphorylated nucleotide such as GTP).

The y-axis is related to free-energy, and is comprised of the classical equations linking16 voltage and capacitance to free-energy*. The x-axis is time (T), It can be seen that the charge and discharge of a mitochondrion occurs over time as a near square wave.

The frequency of discharge then determines the energy expended per unit of time, that is it is power(P) output of the mitochondrion. The height of the discharge wave is related to the amount of energy stored

and so is capacitance(C).

Figure 1:

A set of charge-discharge curves for a mitochondrion-capacitor showing showing increasing levels of charge

leakage (uncoupling). It takes increasingly longer to reach the required membrane potential for a given supply

of substrate-derived electrons/protons. Ultimately the threshold potential will not be reached and then

mitochondria will depolarise triggering apoptosis.

Figure 2:

A series of charge’discharge curves as energy is drawn off the mitochondrion in response to demand.

The rate at which work (charge/discharge)  can be done is a measure of the power output of the mitochondrion.

The red lines represent the charge/discharge curves of an older ‘leakier’ mitochondrion.

Less power is available.

Power output.

The diagram in Figure 2 shows the ‘beat’ of a mitochondrial power curve.

Mitochondria are known to oscillate over a range of time periods,

slow  being 4 minutes and faster 20 seconds17.

Mitochondrial cytochromes can also absorb light in the NIR range at about 800nm this is at TeraHz frequencies!18

Capacitance notes: 

For a given supply of substrate-derived electrons/protons the time to reach the required membrane potential depends on the magnitude of the capacitance ( ie amount of energy that can be stored) and the amount  of charge leakage. A smaller capacitance would be an adaptive response to a mitochondrion that is struggling to reach the membrane potential threshold for ATP synthesis.

Possible uncoupling mitigation strategies:

An adaptive response to uncoupling as threshold voltages become harder to reach would involve a decrease in the surface area of the inner mitochondrial membrane in order to reduce energetic capacity but still be viable in the production of ATP. Other mitigating strategies could involve a decrease in the dielectric constant of the inner membrane by changing the lipid composition and/or stimulation of mitochondrial activity by substrate supplementation ( eg acetyl-carnitine, malic acid). Mega mitochondria often obserevd in senescent cell with fewer internal cristae probably represent an attempt to stay viable though in a low power state16.

Ref:

1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18

Three Parent Children: Mitochondria, Ageing and the Third Party

 

Three parent families: Mitochondria, Ageing and the Third Party

mtDNA sequencing shows  mutational differences when mtDNA of super geriatrics is compared to that of ‘normal’ folk. This is exciting because it contrasts with the past failures to find differences in nuclear DNA for these populations and mitochondria a important to the ageing process. A global pan species mtDNA sequence database has been setup to collects and collate these data.

I think, increasingly, the centrality of mitochondria in the ageing process is not in dispute. Their reproduction, number, size and electrochemical integrity links directly to the well being and longevity of a cell, an organ and ultimately the organism.

The three parent embryo has made headlines recently in the treatment of mitochondrial disease. The concept is simple, mitochondria are only inherited from the maternal line via her eggs and if her mitochondria carry a mutation which causes a disease it will be passed on to a child. The answer to the problem is to remove the disease carrying mitochondria from the egg and replace it with ‘normal’ mitochondria from a female donor’s egg.

The above provides a scenario for genetic engineering, eugenics. There are millions of human eggs frozen and in store. This has been going on for about forty years and the average age of the donor is nearly forty years old. Some donors if alive are approaching the age of seventy plus where super-geriatric traits are emerging. Potentially then mitochondria from their frozen eggs can be transplanted into eggs depleted of diseased mitochondria.

A race of supergeriatrics could be engineered. 

Unethical, for sure, will it be done?

Surely, the narcissitic super-rich could not resist it for their special offspring?

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.