A restored classic car may look and run well but it’s not fresh off the production line. It will have been repaired umpteen times, and it is not about to be thrashed around the track … except maybe on special occasions. Such is the nature of the rejuvenated.
This analogy serves well enough to illustrate the current thinking in the pursuit of longevity and the preservation of youth. From the cosmetic (a respray), the physiological fitness plan (new suspension and bearings) to the subcellular diet-related (an engine overhaul), all cases of ‘rejuvenation’ are synonyms for repair. I am interested in repairing biochemical engines, which in the case of aging organisms means mitochondria.
To get started I need to set out some ground rules regarding my picture of mitochondria. A picture I have set out in previous posts. To me they are tiny electronic devices. They can conduct electrons and physically separate charges to create potential differences measured in volts. Their membranes have low dielectric constants and large surface areas so can store charge as does a capacitor and like capacitors they leak a little charge too. Finally, they can (controllably) collapse their charge-gradient and transform that energy into chemical form … or else they can be ‘shorted out’ releasing their energy as heat.
Or, in biochemical jargon: the process of oxidative phosphorylation and electron transport generates a membrane potential and a proton gradient, the energy of which is used to synthesise ATP unless it is ‘uncoupled’ by something that makes the inner membrane permeable to positive ions.
My ‘electronic’ mitochondria reduce biochemical complexities to simpler axioms which include making sure that voltage and capacitance remain high and charge leakage remains low.
To do this we must:
- Keep the processes that separate charge going flat out.
- Maintain the dielectric integrity of the membranes.
- Maintain the surface area of the mitochondria and hence its capacitance
- Stop leaks.
It has been known for a long time that stimulating the mitochondria by feeding them their favorite food 1 (acetyl units) and transporting them using a the so-called carnitine shunt using the food supplement acyl-carnitine peps up the activity of the electron transport chain. Ditto foods like malic acid and citric acid speed up the citric acid cycle. Such supplements address the first point in the list above but all will be wasted if the other points are not. ‘Revving up in neutral’ will generate heat but not a lot of action.
As we age mitochondria change, a proportion of them become larger with fewer christae 2, They leak proteins more easily 3,4 and eventually depolarise completely leaking the fatal Cytochrome C which leads ultimately to cell death. I also proposed that larger mitochondria are an adaptive response to reduce capacitance in order to maintain the threshold membrane potential for ATP synthesis. But what to do about this?
In a previous blog I referred to my work showing that Cytochrome C leakage was reduced in rats fed a diet high in cholesterol.4 Cholesterol rich membranes also have a higher dielectric constant than cholesterol depleted membranes. This is a start, a repair of sorts but what we really need is something to:
a) purge from the cell inefficient and downright dangerous larger mitochondria struggling to maintain their membrane potential against a backdrop of increasing leakiness.
b) plug the leaks.
When the Cats come out.
Metal cations are positively charged metal atoms and cells use different ion gradients to power various energetic processes such as nervous conduction (Sodium and Potassium (Na+, K+), kidney function (Na+, K+ and H+), mitochondrial energy production (Proton H+) and muscle contraction (Calcium Ca++).
But what about the physiological effects of other cations, cations not normally present in high quantities in the food we eat? Specifically I mean very small cations that can, could, or do interfere with the ions above by virtue of their small radius and ability to get into cells and bind to membranes. That is cations small enough and rare enough to be ‘mistaken’ for the usual suspects.
My short list comprises: Lithium, Beryllium, Boron, Aluminium and Germanium ( Li+ Be++, B+++, Al+++, Ge++) on the basis of their ionic radii shown in the Periodic Table5.
Yes, all are poisonous (very) all are very small and they all affect mitochondria causing them to enlarge and uncouple. Germanium induces mitochondrially mediated apoptosis6; aluminium caused an increase in mitochondrial free radical (ROS) production7; beryllium uncouples and cause them to swell.
Two of them though, in low doses, bizarrely increased the lifespan of short lived organisms8,9. These are Lithium and Boron, now that is interesting. Lithium increased the autophagy ( absorption) of enlarged dysfunctional mitochondria and another author10 speculated that ion channels were blocked by the unusual ion helping to reduce charge leakage and maintain membrane potential when he found enhanced mitochondrial activity in human brain tissue.
Boron also decreased the size of the mitochondrial population making them more elliptical. The experimental animals were: C elegans (a nematode worm) and Drosophila (a fruit fly).
I am intrigued. Plugging leaks and culling the weak would be close to top of my list of repairs to mitochondria. A lot more pieces of the jigsaw need to be found but in the meantime what food would benefit me most according to the repair schedule set out in this blog.
I would get my dietary cholesterol or its precursor squalene from foods naturally rich in it such as oily fish, seafood and olive oil. Of foods with a high lithium content, pistachio nuts are prominent and for boron, walnuts and dark greens like kale. For a boost in activity I would make sure I got my fructose, malic acid or citric acid from fresh fruit. Ok that looks quite a lot like the perfect Mediterranean diet...I wonder why they live so long and have such low rates of dementia?
1)Ann N Y Acad Sci. 2004 Nov;1033:108-16.Delaying the mitochondrial decay of aging with acetylcarnitine. Ames BN1, Liu J.
2) Antioxid Redox Signal. 2010 Feb 15; 12(4): 503–535. Mitochondrial Turnover and Aging of Long-Lived Postmitotic Cells: The Mitochondrial–Lysosomal Axis Theory of AgingAlexei Terman,
1 Tino Kurz,2 Marian Navratil,3 Edgar A. Arriaga,3 and Ulf T. Brunk2
1 Tino Kurz,2 Marian Navratil,3 Edgar A. Arriaga,3 and Ulf T. Brunk2
Author(s): SPENCER, JA; HORTON, AA EXPERIMENTAL GERONTOLOGY Volume: 13 Issue: 3-4 Pages: 227-& DOI: 10.1016/0531-5565(78)90016-5 Published: 1978
4) Differential Effect of Digitonin on Liver Mitochondria from Old and Mature Rat Spencer, John A.; Horton, Alan A. BIOCHEMICAL SOCIETY TRANSACTIONS Volume: 7 Pages: 673-675 DOI: 10.1042/bst0070673 Part: 4 Published:AUG 1979
6) Neurosci Lett. 2006 Feb 27;395(1):18-22. Epub 2005 Nov 9.Cochlear damage due to germanium-induced mitochondrial dysfunction in guinea pigs.Yamasoba T1, Goto Y, Komaki H, Mimaki M, Sudo A, Suzuki M.
7) Aluminum induces neurotoxicity by altering mitochondria of brain cells
Thursday, January 30, 2014 by: Thomas Henry
8) Effects of lithium on age-related decline in mitochondrial turnover and function in Caenorhabditis elegans. Tam ZY1, Gruber J2, Ng LF3, Halliwell B3, Gunawan R4.
9) Biull Eksp Biol Med. 1990 May;109(5):492-4.[Morphometric characteristics of hepatocyte mitochondria during internal administration of boron-containing water].Korolev IuN, Panova LN, Zhukotskiĭ AV, Butusova NN, Kogan EM.
10) Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissueMaurer IC1, Schippel P, Volz HP.J Gerontol A Biol Sci Med Sci. 2014 Jul;69(7):810-20. doi: 10.1093/gerona/glt210. Epub 2014 Jan 7
