Did human hairlessness allow natural photobiomodulation 2 million years ago and enable photobiomodulation therapy today? This can explain the rapid expansion of our genus’s brain
Introduction
Present hypotheses [1], [2] attempting to explain human hairlessness seem inadequate; they do not confer any immediate benefit on the hairless, neither do they do anything to explain the explosive increase in volume of the human brain over the last 2my – see Fig. 1. The question of hairlessness has been a problem since the time of Charles Darwin [1].
The present leading theory, proposed by Jablonski [2], [3], suggests that the human lineage had become hairless by 1.6mya and that hairlessness allowed the development of additional sweat glands to permit evaporative cooling in times of heat stress. Jablonski envisages hairlessness occurring as a gradual process so that as body hair decreased, the density of sweat glands increased [4]. It could perhaps be seen as a gradual adaptation which mitigated heat stress as hairlessness increased.
Jablonski and Chapman [3], [4] have also pointed to evidence for photolysis of the vitamin folate by ultraviolet radiation (UVR). UVR is higher in the tropics and at higher altitudes. A recent investigation in Brisbane, Australia, at latitude 27° S has confirmed a significant, up to 20%, reduction in folate levels by UVR photolysis in women of child-bearing age [5]. This is despite a contrary finding [6] from Oslo (latitude 60° N) – possibly latitudinal UVR differences played a part. Deficiency of folate in pregnancy is linked to neural tube defects and anencephaly at birth, and to megaloblastic anaemia in later life, which has led to the folate fortification of food in developed countries.
When hairlessness occurred in Africa, Jablonski assumes the bare skin to have been a pinkish colour [2] so that the development of a “dark skin was presumably a requisite evolutionary follow-up to the loss of our sun-shielding body hair”. If so, it would be protected by immediate pigment darkening, which has been shown to be due to ultra-violet-A-mediated expression of the visual photopigment rhodopsin in skin melanocytes, resulting in the rapid formation of melanin [7]. This is followed by a delayed tanning reaction [4]. The iconic ebony skin of the African was then set in stone by a mutation at the MC1R locus which has persisted to this day; but the high number of non-synonymous mutations at the MC1R locus in Eurasians compared with Africans is seen as evidence of adaptive evolution to a paler skin in Eurasians [8] to maintain adequate vitamin D synthesis.
Looking for alternative solutions to explain human hairlessness, one might wonder whether vitamin D could be involved. Its synthesis starts when UVB of 297 nm interacts with 7-dehydrocholesterol in the skin so that levels of this essential nuclear hormone would presumably have increased with hairlessness. The vitamin D receptor (VDR) is a ligand activated transcription factor which is widespread throughout the brain, skin and other tissues. Calcitriol, the end product of vitamin D synthesis, binds to the VDR thereby affecting the expression of hundreds of other genes [9], [10] particularly in the brain. Vitamin D deficiency has long been known as the cause of rickets, but deficiency can also cause a host of non-classical effects such as painful weakness of the proximal muscles [11] and an almost four times greater chance of requiring Caesarian section in childbirth [12]. Vitamin D tends to suppress innate immunity and early life deficiency may be associated with later autoimmune conditions [13].
Calcitriol stimulates neurogenesis in the developing rat brain and promotes myelination, synaptogenesis and neurotransmitter release through its control of intracellular calcium [14]; VDRs have been identified in oligodendrocytes and Schwann cells, both of which are involved with myelin formation. Through its promotion of neurotrophin secretion and control of intracellular calcium, calcitriol influences development and function of the neocortex as well as the more primitive areas of the brain [14].
Two studies [15], [16] found correlations between low vitamin D levels and cognitive decline in the elderly while a recent larger study has extended the correlation to include all forms of dementia [17]. Schizophrenia is significantly more common in dark skinned migrants to higher latitudes, and in urban environments. Infants born in winter and spring are significantly more prone to later schizophrenia, possibly connected to low levels of vitamin D in the last trimester of pregnancy, or to maternal winter viral infections such as influenza. In rats, gestational vitamin D deficiency can cause neurological abnormalities suggestive of schizophrenia [18]. Concluding their in-depth review, McCann and Ames [14] said: “Evidence that vitamin D is involved in brain development and function is strong.” Vitamin D has played a part in brain evolution, particularly in the development and connectivity of the huge number of additional myelinated neurons required to form the neocortex of modern humans – see Fig. 1.
It is certainly beneficial to have additional mechanisms, such as sweating, to keep the brain temperature within optimal limits. However, the additional eccrine glands were not a direct response to hairlessness but perhaps an adaptive response to overheating on the expanding savannah. Hairlessness itself has downsides (see below) so that such a momentous event would necessarily need to be accompanied by immediate beneficial consequences otherwise the hairless mutation/s would quickly succumb to negative selection. Jablonski suggests [2] that “naked skin itself played a crucial role in the evolution of other characteristic human traits, including our large brain…” but does not explain exactly how this may have occurred. It seems unlikely that an increase in eccrine glands could, in itself, account for the great increase in brain size that occurred in our genus in the past 2my – see Fig. 1. Likewise, although increased levels of vitamin D would be advantageous for building a large brain, it would take many generations before the benefits would be apparent, by which time any evolutionary pressure to maintain hairlessness would have long disappeared. So increased levels of vitamin D were fortuitous and its genetics do not appear to have played any role in the initiation of hairlessness. Neither the evaporative cooling theory nor the vitamin D scenario confers an immediate benefit. A theory is required where some immediate advantage occurs concomitantly with hairlessness. Such a theory is elaborated in the rest of this paper; this theory can explain how hairlessness initiated the huge increase in the brain volume of our genus over the past 2my [Fig. 1].
In mammals the energy required to maintain body temperature is generated by the catabolism of energy stores and presumably hair in mammals developed as an adaptation to conserve endothermic heat. So to maintain temperature after the loss of insulating hair will entail an energy deficit when the ambient temperature falls much below 37 °C such as in Africa 2mya during cold nights on the increasingly open savannah – or even in a tree or a cave. How could such an apparently deleterious genetic mutation have been so successful? What beneficial attributes could hairlessness possibly confer?
Could hairlessness perhaps allow a type of light-mediated energy synthesis? This is not such an outlandish idea – indeed it seems the only plausible explanation. It is already known that low levels of red and near infrared radiation (R&NIRR) acting on hairless human tissue can stimulate the production of ATP, the universal energy currency of life on our planet. Low levels of R&NIRR are the basis for the non-invasive medical treatment known as photobiomodulation (PBM) [19], or low-level light therapy (LLLT). PBM should not to be confused with photodynamic therapy or with the burgeoning invasive science of optogenetics. In the correct dosage, PBM appears to be beneficial in a wide range of conditions such as wound healing, osteoarthritis and tendonopathies [19], also myocardial infarction [20] and particularly in neurological conditions such as neck pain [21], and, transcranially, for embolic stroke [22], severe depression [23] and chronic traumatic brain injury [24] – more later. The effects of PBM are however biphasic or hormetic – if the irradiance is increased beyond an optimal point, the benefits can decrease. PBM has similarities with other non-invasive therapies: transcranial magnetic stimulation and the related technology transcranial direct current stimulation. All three are effective in treating similar conditions, which is not surprising since they all ultimately appear to be forms of non-invasively inducing electrons in the electron transport chains (ETC) of the underlying nerve cells. All result in ATP extrasynthesis and significant alteration in the expression of over 100 genes [25], [26]. The direct current stimulation did have some safety issues initially [27] – convulsions and syncope had been reported – but these have been overcome. A recent groundbreaking paper in humans [28] focused transcranial magnetic stimulation on a cortical area identified as having strong connections with the left hippocampus; this improved tests of associative memory. The right hippocampus appeared to function differently.
In animals, the main mechanism for synthesising ATP is the process of oxidative phosphorylation (oxphos) in the mitochondria of cells. In humans, brain neurons favour glycolysis as an energy source perhaps connected with the abundance of glucose transporters in the walls of the arteries and arterioles supplying the brain. Oxphos consists of four protein enzyme complexes (excluding the final enzyme ATP synthase). In a series of redox reactions, electrons are passed extremely rapidly from one complex to the next, down the ETC liberating Gibbs free energy and storing it as an electrochemical gradient by pumping protons across the inner mitochondrial membrane. These protons are then used by ATP synthase to generate ATP. The ETC of oxphos has similarities to the extremely efficient first stage of photosynthesis.
The exact mechanisms by which PBM exerts its effects are still incompletely understood [29], [30]. However it is known that R&NIRR is absorbed by complex IV of oxphos, cytochrome c oxidase (COX), in the mitochondria of cells. Nitric oxide (NO) and reactive oxygen species (ROS) are generated intermittently. NO and ROS are both recognised signalling molecules. Lane [31] states “The immediate effect (of R&NIRR) is an energy buzz in which ATP levels are stoked up… A few hours later, the activity of 110 genes shifts in concert.” Pastore et al. [32] prepared purified COX showing it to be a mitochondrial photoacceptor and proposed that the red laser light which he used interacted directly with metal ions (haem-iron, copper, zinc or magnesium) embedded in the COX protein. There are at least five absorption peaks in the spectrum for COX; these are around 405, 625, 680, 760 and 820 nm [33]. PBM is normally administered by laser or non-coherent light emitting diode (LED) around one or more of the longer peaks (which have greater penetration depth).
PBM involves increased activity in the oxphos ETC resulting in increased amounts of ATP (ATP extrasynthesis). The genetic effects of PBM involve the activation of the redox-sensitive transcription factor NFkB which then affects the expression of 111 downstream genes in ten different functional groups [25]. Overall NFkB is also involved in brain plasticity, learning and memory and plays a role in response to infection, regulating innate and adaptive immune genes.
Hamblin writes [34]: “The absorption of photons by molecules leads to electronically excited states, and consequently can lead to an acceleration of electron transfer reactions. More electron transfer necessarily leads to more production of ATP.” Yu et al. [35] express a similar concept. Light absorbing molecules usually dissipate their acquired energy as heat. But some don’t, such as the absorbing molecules in the photosynthetic and respiratory chains: these were specially selected by evolution 2.4bya or more [36] for their ability to engage in biologically useful functions such as electron transfer. Oxphos and the first phase of photosynthesis are similar processes in that both employ an ETC using various cytochromes to produce ATP very efficiently (although the overall efficiency of photosynthesis is reduced for other reasons). In hairless humans, there is no reason why the ETC of oxphos should not be powered by electrons energised by light photons as well as those from NADH and FADH2 from the Krebs cycle. Indeed this is the basis of PBM. And humans are not the only animals to use light to synthesise ATP. An aphid is reported [37] to synthesise its own carotenoid photoacceptors to produce light-generated electrons to pass down its ETCs. A hornet [38], [39] may also use light to generate extra ATP.
It is known that R&NIRR can penetrate several centimetres below the skin [31] and can thus enable ATP extrasynthesis in the superficial limb muscles. It has recently been shown that low levels of NIRR at 810 nm can activate latent transforming growth factor β1 and so initiate the differentiation of human dental stem cells [40]. It is more difficult for R&NIRR to penetrate the skull-bone but neurons are easily excited and fluences as low as 0.1 or 0.2 J/cm2 are reported to be effective as PBM for the human cerebral cortex [24], [41]. If hairlessness is to be seen as a useful adaptation, one might wonder why we have a large scalp area directly exposed to the sun, but covered with light-scattering hair. It seems likely that hairlessness was initially complete, but male beards and scalp hair developed later as a sexual discriminant – beard growth and male pattern baldness are known to be controlled by dihydrotestosterone as well as the hairless gene Hr.
The following brief summaries demonstrate the effects of PBM delivered transcranially to animals and humans. In strokes induced by cerebral embolisation in rabbits, Lapchak and De Taboada [22] showed that embolisation reduces ATP levels in the affected cortex but also showed that PBM can significantly restore these levels. In experiments with fear-conditioned rats, Rojas et al. [42] found that PBM increased COX activity and also increased oxygen consumption in the prefrontal cortex. COX activity was still significantly elevated 24 h after the PBM, and the rats’ ability to extinguish fearful memories and prevent their recurrence was enhanced. Increased cerebral blood flow is a necessary accompaniment in order to supply the extra oxygen required as a result of the PBM: Lin et al. [43] did find this in their work on methylene blue using a human hippocampal cell line. Methylene blue is a synthetic electron carrier which they showed increased mitochondrial function with significant increases in cerebral blood flow, brain glucose uptake and oxygen consumption. These papers, [42], [43], demonstrate the concept of cerebral metabolic and haemodynamic enhancement resulting from PBM’s action on the brain. It is suggested that this would have originally occurred as the daily consequence of natural R&NIRR at dusk after hairlessness appeared and would result in a great evolutionary advance.
In analogous work in humans, repeated PBM was used transcranially by Naeser et al. [24] for the convincingly successful treatment of two subjects with chronic traumatic brain injury – LED lights at 633 and 870 nm were used after carefully parting the hair under the LEDs. Studies on post mortem calvaria showed that only 0.2% or 0.3% of the NIR photons penetrate to the white matter [24]. On this basis the fluence at the cerebral cortex was 0.24 J/cm. If Naeser’s results [24] can be replicated with larger numbers, this would surely validate the efficacy of PBM as a mainstream cost-effective treatment for otherwise treatment-resistant conditions such as chronic traumatic brain injury and post traumatic stress disorder.
Previous work on severe depression has shown that electroconvulsive treatment and transcranial magnetic stimulation were of approximately equal efficacy, but a small trial of single treatments with PBM [23] compared favourably with both these modalities and it was recommended further investigation be carried out. Interestingly, Timonen et al. [44] in an uncontrolled study of bright light treatment for seasonal affective depression (SAD) in Finland at latitude 65° N, treated 13 patients with bright light given via LEDs in the ear canals, challenging the received wisdom that SAD light treatment could only operate via visual opsins. Treatment was given 5 times weekly for 4 weeks and 10 of the 13 patients achieved full remission (Hamilton depression score < 7). In another SAD study, Avery et al. [45] found that illumination by ‘dawn simulation’ was more effective than either bright light or ‘placebo’ (a dim red light) but surprisingly the bright light and the dim red placebo were equally efficacious. PBM has also been delivered to the underside of the brain via the nose [46], the ethmoid plate being thinner than the skull; the basal ganglia, for example, are more easily irradiated nasally.
Chen et al., [30] irradiated mouse embryonic fibroblasts with 810 nm NIR laser light at fluences ranging from 0.003 to 3 J/cm2. This showed a large increase in ATP synthesis between fluences of 0.03 and 0.3 J/cm2, declining to baseline after some hours. They also showed that NFkB is activated by the generation of laser-induced ROS – the addition of antioxidants inhibited the NFkB activation as well as the ROS, but not the ATP extrasynthesis. They suggest that the laser light increases electron transport to the point where leakage occurs producing ROS. The metabolic effect of the light (the ATP extrasynthesis) is almost immediate, but the genetic effects are delayed. The genetic effects require a signalling mechanism (the ROS) and involve the translocation of NFkB to the cell nucleus, whereas the ATP extrasynthesis occurs entirely in the mitochondria due to NIRR acting directly on the photoaccepting complexes of oxphos. However the genetic effects do also beneficially affect ATP production since this increase continues long after the light is extinguished: as Lane says [31] the downstream genes which NFkB controls, “orchestrate a prolonged rise in mitochondrial energy production”. Proportionate to its size, the brain uses huge amounts of ATP, and it is proposed here that these increased amounts were first generated in the brains of a few related and hairless early members of our genus by the R&NIRR of ancient African sunsets. This also allowed the cerebral metabolic and haemodynamic enhancement discussed above.
Section snippets
The Hypothesis
It is proposed that, around 2mya, a random mutation or series of mutations in an early Homo species rendered a few related individuals completely hairless. Instead of succumbing to negative selection as disadvantageous mutations normally do, they underwent a rapid selective sweep. Why? Because the mutation/s also conferred a huge advantage which greatly outweighed the minor disadvantage in Africa at that time. As PBM research shows, it allowed the extrasynthesis of ATP energy and also allowed
Further considerations
It should be mentioned that large quantities of ATP are carried by red blood cells (RBCs) [47]. On reaching the capillaries some of this is released into the plasma as a vasodilator and a signalling molecule, and any excess is degraded by the plasma enzyme ectoATPase. The ATP is assumed to be produced by substrate phosphorylation. RBCs have no nuclei or mitochondria, but they do carry mRNA transcripts of 1019 genes [48] with more than half of these concerned in cellular metabolism. Haem is a
Testing the hypothesis
The human body turns over its entire weight in ATP each day, although at any one moment it contains only 250 g. ATP is a very evanescent molecule, which is quickly used up or converted into other high energy compounds or banked as phosphocreatine [58]:
Phosphocreatine can be used as a rapid source of ATP when required by muscles. In vivo methods for tracking high energy molecules such as 31phosphorous magnetic resonance spectrometry and NIR spectroscopy
Discussion
Assuming significant quantities of ATP are synthesised and brain energy and genetic expression changes occur as expected, this should be related to the fact that these early Homo people are envisaged as being active in dappled savannah sunlight for most of the 12 daylight hours. For the hairless ones, the extra ATP and the cerebral advantages would greatly improve their hunting abilities, giving them a big competitive advantage and allowing them to add more animal protein to their diet. When a
Summary
As a result of research into PBM and the effects of R&NIRR it is proposed that the primary spark for the last 2my of human brain evolution was hairlessness, which allowed ATP extrasynthesis and cerebral metabolic and haemodynamic enhancement. This drove the very rapid brain expansion in an evolution that started around 1.8mya. While the Pleistocene climate was still equable 2mya, there was an immediate advantage in becoming hairless in Africa – it allowed ATP extrasynthesis and natural PBM at
Conflicts of interest
The author has no conflicts of interest and no source of funding.
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