“Each stage of evolutionary history has its characteristic metabolic chemistry. By protecting and promoting mitochondrial respiration we are contributing to our own evolution.”
Part 1: Mojo and Mitochondria.
Mitochondria are the organelles responsible for energy production in the cell, it is within the mitochondria where food, in the form of carbohydrates, fats and protein, is oxidised to produce energy. The metabolism of glucose involves a step that happens outside of the mitochondria and without the need for oxygen, glycolysis which converts glucose to pyruvate, pyruvate then enters the mitochondria, where it is converted to acetyl-CoA which then enters the citric acid (Krebs/TCA) cycle where it is oxidised producing carbon dioxide, and water, NADH, enters the electron transport chain and is oxidized to NAD+, in healthy cells there is a high ratio of NAD+ to NADH, increased NADH is found in multiple diseases including diabetes and cancer. The citric acid cycle is the key pathway that is common to carbohydrate, fat and protein metabolism. For each molecule of glucose 2 ATP are produced during glycolysis, and around 30 molecules of ATP from the mitochondrial phases, in theory more ATP could be produced but some degree of uncoupling usually occurs. If there is a lack of oxygen or something inhibits mitochondria pyruvate will be fermented to lactate.
Mitochondria in addition to being the site of energy production have other roles, they are involved in hormone production and response, being the site where cholesterol is converted into protective steroid hormones such as pregnenolone, progesterone and DHEA. Mitochondria play roles in cell identity and differentiation. They can vary in size and shape from simple rod and elliptical structures to complex extensive interconnected networks in cells with high energy demands such as muscle cells of the heart and diaphragm. These variations in size, shape and location are all responsive to changes in demands placed on their cells. Their activity is involved in generating a formative field.
The extensive mitochondrial networks result from an increase in mitochondrial fusion, simpler mitochondrial structures from fission processes. A balance between fusion and fission is essential to cell function, imbalances in either direction can cause problems. Generally fission (fragmentation) of mitochondria results in a decrease in oxidative metabolism, increased fission is associated with cell division, dedifferentiation, apoptosis, lowered cytochrome oxidase (a fundamental respiratory enzyme), increased glycolysis, and a range of diseases including diabetes, Huntington’s, and cancer. Fission is increased by high glucose levels, perhaps as it allows for increased glycolysis and pyruvate uptake if sustained it seems likely to encourage the fermentation of pyruvate into lactate. Glucose deprivation enhances mitochondrial fusion.
Increased Mitochondrial fusion is associated with increased oxidative respiration, increased cytochrome oxidase, increased cell differentiation and specialisation. Denervation and disuse of tissues increases fission, use increases mitochondrial fusion (Iqbal et al. 2013).
Mitochondrial volume and activity decrease with aging, (Ratel et al. 2008). Mammals have more mitochondria than reptiles as well as more active mitochondria, with these mitochondria taking up a greater volume of their cells, some mammals having a sixfold greater oxidative capacity than reptiles (Else and Hulbert 1981).
Part 2: Accelerated Adaptation.
“A proposed law of aromorphosis: that the retardation of the flow of energy in living systems tends toward a maximum; in animals this would imply a trend toward larger-brained, longer lived and probably warmer animals, having a higher energy charge.”
Human Accelerated Regions (HARs) are segments of the human genome that are conserved extensively within vertebrate evolution but are strikingly different in humans (even when compared to chimpanzees). They were identified by Katherine Pollard and other researchers, 202 HARs were identified with 49 of them being considered highly significant. They are numbered according to their degree of difference from chimpanzee equivalents, HAR1 being the most different (Pollard et al. 2006). Their striking degree of difference suggests that they have undergone a particularly rapid evolution, suggesting that conventional ideas about evolution as a slow mechanical process may need to be reconsidered.
HAR20 codes for the protein peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1A), this makes it unusual among the human accelerated regions (HARs) as most of the others are non-coding, they do not encode proteins, non-coding DNA has previously been described as junk DNA, it makes up 98.5% of the human genome.
PGC-1A both induces mitochondrial biogenesis (increasing mitochondrial volume, and creating new mitochondria), and modulates the composition and function of individual mitochondria.
PGC-1A was originally discovered in brown fat cells, brown fat contains more mitochondria than white fat, increased levels of BAT (brown adipose tissue) are found in children. PGC-1A can increase mitochondria in white adipose tissue converting it to brown or beige (intermediate between white and brown). Exposure to cold can increase PGC-1A.
PGC-1A increases mitochondrial mass and oxygen consumption, lowered mitochondrial function is involved in multiple diseases some of these may involve impaired PGC-1A including Huntington’s, Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).
PGC-1A can be increased by muscular activity especially endurance activity. PGC-1A both causes the conversion of type 2 fast white glycolytic fibres to type 1 slow red oxidative fibres, and is expressed at higher levels by type1 red oxidative fibres with increased mitochondrial density, extensive capillary supply and increased nerve supply (Lin et al. 2002). Type 1 fibres are those fibres that are involved in maintaining body posture as their constant activity requires intense respiratory support, type 2 fibres are capable of exerting more explosive force but they lack the fine motor control of type 1. An increased ratio of type 1 to type 2 fibres is present in humans compared to our primate relatives.
More on muscle and metabolism here:
PGC-1A increases oxidative metabolism but lowers reactive oxygen species production (ROS) inducing the expression of ROS lowering enzymes (Austin and St. Pierre 2012).
PGC-1A increases UCP1 and mitochondrial uncoupling, uncoupling is an incompletely understood phenomenon where oxidative metabolism and oxygen consumption is uncoupled from ATP production, it is sometimes considered a wasteful process but it appears to be beneficial. One of the main sites of uncoupled respiration is brown fat where it acts to increase heat production, however heat production might not be it’s main function as often a significant amount of respiratory energy (in rats 20-25%) goes into uncoupling (Brand 2000). Uncoupling may also increase longevity, mice with the highest metabolism, most uncoupling had 17% higher oxygen consumption used 30% more energy and lived 36% longer than mice with the lowest metabolism (Speakman et al. 2004). Uncoupled mitochondria produce increased carbon dioxide as a result of their increased oxygen consumption.
Uncoupling is neuroprotective, protecting against excitotoxicity and reducing damage in the cortex by around 50% after traumatic brain injury (Maragos and Korde 2004).
Predictably mammals have more mitochondrial uncoupling than reptiles (Akhmerov 1986).
Uncoupling is associated with increased mitochondrial fusion ( Golic et al. 2014). PGC-1A promotes the expression of Mfn2 a protein involved in mitochondrial fusion.
Uncoupling increases mitochondrial oxygen consumption and lowers ROS, I think this supports the idea that oxidative metabolism is in some sense like a whirlwind, potentially self-intensifying. An increased metabolism coheres the respiratory apparatus, electrons (energy) travels through it without escaping to react inappropriately as might happen when less intense producing ROS. Alternatively the intense metabolism could be likened to a fierce flame burning bright without smoke, a less intense metabolism would be like a faint flame forming filthy fumes.
The increased carbon dioxide produced by uncoupled mitochondria dilate blood vessels assisting in bringing increased blood flow and oxygen, generally acts to protect proteins from oxidation and increase the coherence of the organism (Ray Peat has written extensively on the biology of carbon dioxide, there are a couple of articles on this site also).
The natriuretic peptides released by the heart when it is stretched by increased blood flow act in part by increasing PGC-1A (Engeli et al. 2012).
More on the natriuretic peptides here:
Deletion of PGC-1A results in vascular aging and atherosclerosis as well as decreasing telomerase reverse transcriptase (TERT), telomere shortening is involved in DNA damage, mitochondrial dysfunction, multiple diseases and general aging. TERT maintains telomere length, telomeres are the regions at the ends of chromosomes that protect the chromosome from deterioration or fusing with neighbouring chromosomes. Telomeres shorten during cell division. PGC-1A increases TERT, restoring telomere length ( Xiong et al. 2015). *BANG* What was that sound? Oh I think that was the final nail in the coffin of the Hayflick limit.
Low PGC-1A appears to be involved in multiple neurodegenerative diseases, including Diabetes, Alzheimer’s, Parkinson’s, Huntington’s and ALS, increasing PGC-1A appears to be protective and therapeutic against neurodegeneration, PGC-1A increases neuronal mitochondrial biogenesis, and nerve tissue like all highly metabolic tissues usually produces high levels of PGC-1A, thought, perception, intelligence and sensitivity are all dependent on energy.
As mentioned earlier most of the human genome consists of noncoding DNA, less than 2% encodes proteins, the majority of the Human Accelerated Regions (HARs) are noncoding DNA which is transcribed into non-coding RNA, clearly the “junk DNA” has purpose.
HAR1 is the most accelerated region, in humans it differs from the chimpanzee equivalent by 18 substitutions. The chimpanzee differs from the chicken equivalent by only 2 out of 118 bases (Pollard et al. 2006).
In humans the RNA produced from HAR1 assumes a clover leaf like formation, in chimps a simpler hairpin like structure, the chimp and human HAR1 also have differing electro-phoretic mobility (Beniaminov et al. 2008).
Exactly how HAR1 functions is unknown, it is expressed in developing human and primate brains, with its expression pattern matching that of the extracellular matrix glycoprotein Reelin. Both HAR1 and Reelin are expressed primarily by Cajal-Retzius cells during development. HAR1 is also expressed in the testes and ovaries.
Reelin’s primary function appears to be in regulating the development of the cortex of the brain, guiding neuronal cell migration and positioning. Modulating synaptic plasticity and stimulating dendrite development. Decreased Reelin is implicated in schizophrenia, autism, Alzheimer’s, and temporal lobe epilepsy. A total lack of reelin results in the condition of lissencephaly, a smooth brain completely lacking the normal extensive gyrification (the cortical convolutions) of the human brain, resulting in profound cognitive impairment. Lissencephaly often occurs with hypotonia and a lack of unsupported sitting.
As evolution advances and the cortex becomes more complex Reelin expression goes up with human brains expressing the most. In mammals the cortex develops from inside to out producing a multilayer cortex, in reptiles the cortex develops outside to inside producing a single layer cortex (Molnar 2007).
Reelin appears to structure the space for cortical growth, supplementing mice with Reelin enhanced cognitive abilities, synaptic plasticity and dendritic spine density (Rogers et al. 2011). Reelin can also be increased through T3 the active thyroid hormone (Sui et al. 2010).
Reelin’s role as a morphogenic regulator is supported by decreased Reelin expression in cancer, with lowered reelin promoting the migration and invasion of cancer into surrounding tissues (Walter and Goggins 2008). Heme-oxygenase-1 a stress inducible protein responsible for the breakdown of heme, producing carbon monoxide and bile pigments, Carbon monoxide is a respiratory toxin and increased heme-oxygenase damages mitochondria and reduces reelin content of the brain, producing schizophrenia like symptoms, heme-oxygenase is also involved in cancer (Song et al. 2012).
Human Accelerated Regions, especially the top five show a strong bias for adenine and thymine substitution to guanine and cytosine suggestive of a directionality, a similar substitution of adenine and thymine for guanine and cytosine has been found in mitochondrial DNA to correlate with increased longevity (Lehmann et al. 2008).
I think the Human Accelerated Regions are highly suggestive that Lamarck was correct acquired characteristics can be inherited, meaning evolution is not some blind mechanical process that acts upon insensate dead matter, that it is essentially a living sensitive capacity of life. There is evidence that this is the case, Barbara McClintock experimenting with maize plants found that when the plants chromosomal ends (telomeres) were damaged, the cell appeared to be able to sense the damage and bring together the ruptured ends of chromosomes. If only a single (rather than a pair) chromosomal end is damaged repair is made more difficult, McClintock found that the cell would make use of mobile genetic elements that could repair the damage and restructure the genome at various levels. This suggests that the genome is not some inert structure mutating randomly, but capable of at least some degree of sensitivity adapting to challenges in a coherent non-random way (McClintock 1983).
John Cairns studying E.coli that were unable to metabolize lactose, found they were able when grown in media in which lactose was the only source of food to generate the necessary mutation to metabolize the lactose and survive. The rate of evolution was orders of magnitude higher than random chance would allow (Cairns and Foster 1991).
Part 3: Even Effervescent Elves.
“If we optimize the known factors which improve energy production (red light, short-chain and medium-chain saturated fats, and pregnenolone, for example), to the extent that our metabolism resembles that of a ten year old child, I don’t think there is any reason to suppose that we wouldn’t have the regenerative and healing abilities that are common at that age. I suspect that both brain growth and remodeling might proceed indefinitely.”
I’ve written about the starchild skull previously:
The Starchild may represent an early example of some of the evolutionary potential that is available to humans if we can reorient ourselves to a more sensitive understanding of the nature and possibilities of Life.
Our biology (biopsychology) is far more mutable and plastic than the dominant cult of genetic determinism supposes. This has been realised by multiple cultures and subcultures, the various spiritual systems at their core are attempts to promote our highest possibilities. Of course corruption co-option and confusion have occurred over time with some developing into authoritarian control systems that have stifled creativity, imagination and evolution producing sick psychic mono-cultures. Even then the core has usually remained intact.
The elongated skulls found worldwide may represent attempts to actively shape development, changing brain morphology possibly to emphasise certain capacities, these would have involved use of things such as head binding, perhaps these changes in brain morphology produced accumulated epigenetic modifications allowing for after a few generations some of the skulls which appear to have unusually large cranial volumes. The Starchild appears to have a more balanced morphology, and increased neoteny (youthful qualities), and may have occurred as a result of internal modifications rather than external.
The Starchild’s large cranial capacity is suggestive of an intense metabolism, as cephalisation (the relative enlargement of the head and the concentration of the nervous system within the head) in animals proceeds so does metabolic rate. The composition and quality of the Starchild’s bone also suggests an intense metabolism, relative to human bone it is thinner but apparently more durable, being woven through and strengthened by protein (collagen?) fibres, it’s increased carbon content might result from an increased metabolism generating more carbon dioxide, allowing for a change and developmental advance in bone quality. Hypothyroidism (a decreased metabolism) is associated with increased fracture risk and weaker bones. Reptiles have more developed bones than amphibians and mammals still more so resulting not only from metabolic differences, but an increase in the complexity of the forces acting on the bones as a result of increasing nervous system development, mammals generally being more graceful than reptiles.
Cephalisation as an evolutionary trend in animals obviously goes along with increased self-awareness and reflective ability, simpler animals, fish, amphibians, and reptiles, appear to have relatively limited self-awareness, their awareness and energy is focused outwards on basic survival. If function produces structure, then cultivating internal sensitivity, reflective thought, and imagination should assist in developing those structures that support their function.
There are suggestions that conscious awareness can itself intensify metabolism meditators have lower lactate levels suggesting improved oxidative metabolism, denervation increases glycolysis and lactate production, consciousness here appears like a self-intensifying process.
Clear links exist between mitochondrial energy status and gene expression, there are at least two processes involved in gene expression that are strongly influenced by metabolism acetylation and methylation. Histone acetylation is regulated by availability of acetyl CoA produced in mitochondria, generally acetylation activates and promotes genes and deacetylation represses them.
Methylation generally decreases expression of certain genes, various things that interfere with mitochondrial metabolism increase methylation for example hypoxia and BPA (Nahar et al. 2015). Methylation and hypermethylation of various genes (NADH dehydrogenase, cytochrome oxidase and PGC-1A) involved in promoting metabolism is involved in obesity and diabetes (Barres and Zierath 2011).
It was believed that methylation represented a relatively permanent modification, with demethylation limited to relatively passive processes occurring during DNA replication and embryogenesis, however active demethylation has been found to occur quite commonly. Active demethylation is dependent on the availability of metabolites of the citric acid (Krebs/TCA) cycle (Meng et al. 2014).
Respiratory energy production has increased as evolution has advanced allowing for increasing cephalisation and intelligence, if an organism with an intense metabolic rate suddenly found its metabolism lowered all the biological structure dependent on that energy production would degrade including the consciousness, gene expression would change, methylation would increase.
If maintaining our current state is dependent on generating a certain level of energy production then perhaps cultivating a higher level of energy production will help to make possible an increase in developmental complexity. Increased rates of DNA synthesis and nucleotide substitution occur in organisms with higher metabolic rates (Martin and Palumbi 1993). An advance to neo-human perhaps even post-mammalian life may be a real possibility.
The story goes that when Bodhidharma arrived at the Shaolin temple he found monks who were too weak to meditate successfully, so he developed a series of postures and movements linked to the breath (these eventually developed into Shaolin kung fu) for the monks to practice to assist in their cultivation. These exercises would have cultivated type 1 muscle fibres and increased the monks PGC-1A expression increasing their vitality.
The monks could then meditate meaningfully, meditation has been found to increase the gyrification (the convolutions and surface area) of the cortex of the brain (Luders et al. 2012). This increase in cortical gyrification seems likely to involve increased expression of HAR1 and Reelin.
It seems somewhat unlikely to be coincidence that yogic practices just happen to involve the activity of two highly significant human accelerated regions.
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