Nutrition and metabolic disease in humans

Nutrition and metabolic diseases in humans

Whilst drawing definitive conclusions from animal studies alone is not possible, they are often very good indicators of what may be expected in human studies. More research into a metabolic switch in humans is needed, but the significant weight of evidence from animal studies cannot be ignored. Professor Richard Johnson proposes a metabolic ‘survival’ switch would be advantageous for humans in times of food shortage or drought. It would help us survive.

Here I look at the current evidence base which may bridge the gap between the scientific evidence in humans, including the nuances we see, and the concept of a metabolic ‘survival’ switch. A switch which may no longer aid survival when sugar, high fructose corn syrup, refined grains and ultra processed foods are in abundance.

History of metabolic disease and diet

The earliest signs of obesity and diabetes

Archaeological remains showing evidence of dental cavities and diffuse idiopathic skeletal hyperostosis (DISH), whereby the spine pulls to one side with the additional weight, are often suggestive of obesity. For much of history, evidence of obesity and diabetes remain rare. However, there is noticeable evidence of these conditions throughout early history, particularly amongst people of high social status, noticeably the very wealthy, royalty and religious leaders.

As early as 38000 -14000 BP (before present), there is evidence amongst Ice age hunter gatherers, depicting obese or pregnant women (Venus figurines). During this time glaciers advanced, resulting in freezing temperatures, which led to a reduction in available sources of nutrition, extinction of some species and a significant reduction in the population. Figurines from this period are hypothesised to be symbolic of fertility and survival.

Egyptian mummies remains from dating back to 1500BC display signs of DISH and dental cavities as well as skin folds. The Egyptians were particularly fond of honey (which was of high value and common amongst the pharaohs and the very wealthy) as well as bread, cakes and beer (often made with honey too).

Later in time around 500-400BC sugarcane was grown along the Ganges river, quite successfully. Locals used to crush the sugar cane and grind it to make a powder added to drinks. Indian physician Sushruta noted that people who frequently drank it developed signs of diabetes including sweet honey tasting urine (sugar puff wee) and obesity. There were two different presentations, those who were younger and thinner, and those who were older and developed obesity and lived longer than the former. Perhaps very similar to the most common presentations of diabetes we see today i.e. Type 1 and Type 2 diabetes.

Polycystic ovarian syndrome, insulin resistance and androgen excess

Polycystic ovarian syndrome (PCOS) a condition amongst women, now known to be related to insulin resistance and androgen excess, is increasingly prevalent in our society, often presenting with symptoms of excess weight (but not always), facial hair (sometimes but not always) and infertility along with an increased risk of Type 2 diabetes. However, this is not a new condition and medical reporting of androgen excess like symptoms, starting around 400 BC, focused on the appearance of male-like hair growth and features of this condition amongst women, often accompanied by menstrual cessation. Two further pathologies were identified, in the late 17th and early 18th centuries, including adrenal pathologies and sclerocystic ovaries.

The emergence of metabolic disease in England and gout ‘the disease of kings’

Fast forward to the 1600th century, when England controlled the majority of the sugar trade, forming the ‘triangular trade’ of sugar, guns, rum and slaves with both America and West Africa. England loved sugar so much it kept most of it to itself initially. Not surprisingly, obesity, diabetes, hypertension, and cardiovascular disease emerged first in England.

Gout an inflammatory condition, associated with high uric acid and more prevalent amongst males became more frequent in England. Gout was also linked with obesity and amongst people of higher social status such as royalty, the very wealthy and religious leaders who could afford access to sugar, refined foods and ‘umami’ purine rich foods such as beer, shellfish and red meat. Gout had been identified much earlier than this by both the Egyptians and Hippocrates who referred to acute gout of the large toe as ‘arthritis of the rich’ and ‘the disease of kings’.

The increase in sugar, refinement of grains, obesity and emerging diseases

In 1874, the sugar tax was abolished in England and sugar became cheaper and more available to the masses, including the poor. Sugar intake per capita rose significantly, with annual intakes doubling at the beginning of the 20th century and more than tripling in the year 2000.

Additionally, in the Industrial Revolution (1750-1900) milling technologies advanced which meant that whole grains could be finely milled (rather than stone ground) with their bran layer and nutrient lipid core removed, to leave the starchy inside. In the 19th century these refined grains became more accessible and soon after, the disease Beri-beri, characteristic of an abrupt and tripping gait likened to sheep, began to increase rapidly reaching epidemic proportions with a profound impact on morbidity and mortality. Beri-beri was not just one disease, it included a number of variants including acute cardiac beri-beri, Wernicke’s encephalopathy (a cerebral form of beri-beri – more associated with chronic alcohol use today), wet beri-beri (an oedematous variant) and chronic beri-beri heart (chronic cardiac variant). Beri-beri was associated with refined rice intake and areas with high intakes or refined milled wheat. It was later discovered that a loss of a B vitamin, thiamine, an important nutrient for energy (ATP) metabolism appeared to be responsible for this. Synthetic thiamine (also known as thiamin) was later developed and fortification of foods became widespread. Although, fortication with thiamine certainly helped treat beri-beri, not long after more deficiency diseases began to become commonplace. These included iron deficiency anaemia, anaemias of chronic disease, Keshan disease, osteoporosis, pellagra, kwashikor, marasmus and growth retardation (the latter three being forms of protein energy malnutrition associated with famine).

Around the 1940’s it became mandatory to fortify wheat flour in many countries with certain vitamins and minerals. The Green Revolution in the 1940’s meant foods became even less diverse and refined grains from wheat, maize and rice i.e. bread, pasta and white rice, increasingly affordable and available to the masses. As refined grains are less shelf stable, artificial preservatives also began to increase in foods. As foods became more heavily processed in the 1970’s, following the move to a low fat diet, fortification became common place in an attempt to combat increasing nutritional deficiencies and make processed foods seemingly nutritious.

Following the focus on ‘low fat’ diets in the 1970’s, fat has been replaced with sugar and refined carbohydrates. The public health message advocating low fat diets meant substitutes were needed and so fat became increasingly replaced with sugar, high fructose corn syrup (HFCS) and ultra-processed foods. In recent years, evidence from meta-analysis and systematic reviews suggest replacement of saturated fat is important but replacing with refined carbohydrates and sugar appears to confer no benefit and it may even be worse for us. There is no evidence that reducing total fat reduces our risk of diabetes, metabolic syndrome or cancer. Replacing animal foods high in saturated fat, such as red meat, cream and butter, with unsaturated fats such as olive oil, nuts, seeds and oily fish appears to be more important, and may significantly lower our risk of cardiovascular disease, diabetes and some cancers.

Above image source: Johnson, R. et al (2007) – Sugar intake per capita (top line) compared with rise in obesity prevalence (bottom line)

There is an abundance of evidence which suggest Western diets high in sugar, refined carbohydrates, alcohol and salty foods appear to increase the risk of obesity, diabetes, metabolic disease, cancers and Alzheimer’s. These diseases are increasingly being associated with insulin resistance. Additionally, more recent evidence suggests refined grains do not appear to be as beneficial as intact minimally processed whole grains, with evidence showing improvements in metabolic markers, including glycaemic and lipid responses, and improved weight control with minimally processed whole grains.

Fructose – the unique nutrient for fat storage

Fructose is a unique nutrient, it is the nutrient for future energy (via fat storage), compared to glucose, which may be referred to as the nutrient for present energy, for example, walking, talking, thinking, running etc. Fructose can be ingested via the food and drink we consume (mainly from sugar, sugary drinks and ultra processed foods), and it can be produced endogenously (made by our own bodies from glucose and sorbitol, without having to actually consume it), via the lesser known polyol pathway.

Humans are more sensitive to the effects of fructose due to the loss of the ability to produce vitamin C and the enzyme uricase in our primate ancestors. This was caused by mutations in the uricase gene millions of years ago. As a result, humans have higher levels of uric acid and a greater metabolic response to fructose. This mutation likely gave our species a survival advantage during seasonal starvation in the middle Miocene sub-epoch.

Fructose consumption in humans has significantly increased in the last century, additionally uric acid levels in Western populations are higher than less developed and more primitive populations.

The polyol pathway in humans – an existing mechanism for complications of diabetes and a potential driver of the Warburg affect for cancer growth

The polyol pathways is the metabolic pathway which animals use to make more fructose from glucose in preparation for low oxygen conditions. In animals this pathway is activated with ingestion of fructose (component of sugar), high glycaemic carbohydrates, hyperglycaemia and salty foods. It is a way of fermenting glucose to fructose to continue the activation of the metabolic switch. Alcohol can also be metabolised via this pathway.

An intermediate of the polyol pathway is sorbitol dehydrogenase which breaks down sorbitol. This enzyme is present in all human cells except the retina, kidneys and Schwann cells (a variety of cells that keep peripheral nerve fibres alive). It is active at lower levels in the lens of the eye, ovaries, testes and liver. This has already been proposed by scientists as an explanation of why vision, kidney and neuropathy are often the first complications which occur with diabetes, as well as erectile dysfunction and infertility. Indeed, activation of the polyol pathway in obese mice has been shown to induce cataracts, this condition is of increased prevalence in humans who have diabetes.

This pathway has been proposed as a potential driver of the Warburg effect. It is effectively the back up generator in the cell when mitochondrial function is compromised. It has been proposed that it may facilitate the expression of cancer causing cells and aid in their growth and metastases. It has already been established that obesity is linked with increased risk of a number of cancers and aldose reductase is activated in various types of cancer, including liver, breast, ovarian, cervical and rectal cancers. Read the 2020 paper on this proposal here.

Above image displays the polyol pathway. Source: Johnson, Bredeson, Tolan et al, 2023 (with my scribbles highlighting the polyol pathway).

It is not yet known if consumption of high glycemic foods leads to the same effects in humans as it does in mice, specifically the activation of aldose reductase. However, in humans, aldose reductase (the enzyme which triggers the polyol pathway) can be activated through various means, including elevated glucose levels, similar to what we see in mice.

The protective effect of exercise, caloric restriction, hydration, antioxidants and oestrogen

In animal studies, the metabolic syndrome is mitigated by exercise (particularly Zone 2 exercise), caloric restriction and fasting, hydration (minimising dehydration), phytonutrients and the fibre matrix in whole fruit and vegetables (but not fruit juice). High fibre intakes appear to have a protective effect also. They all reduce the risk of cognitive impairment and metabolic disease, however, the mice still develop fatty liver and metabolic syndrome but they live longer. This is exactly what we see in the human evidence, with regards to protective effects of these diet and lifestyle factors.

The hormone oestrogen is thought to provide a protective effect against metabolic conditions in women by increasing urate production and excretion of uric acid. Reduced endogenous production of oestrogen in women has been associated with an elevated risk of raised uric acid and gout. The menopause, whereby oestrogen levels fall, is strongly associated with an increased risk of metabolic diseases including obesity, breast cancer, type 2 diabetes, cardiovascular diseases, non-alcoholic liver disease (NAFLD) and metabolic syndrome. Perhaps this could explain why menopausal symptoms appears to be so debilitating today, with increasing reports of memory difficulties, poor concentration, low energy and weight gain, just as we see in the animal studies.

Evidence of a ‘foraging’ response in humans in response to fructose

Studies have demonstrated hepatic (liver) ATP (energy) depletion following ingestion of fructose in humans. Levels fell by 20% in humans who ingested oral fructose and up to 60-70% in those given intravenous fructose. Additionally, blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) have demonstrated reduced blood flow to cortical control areas of the human brain following intravenous fructose. The cortical control areas are associated with emotion, processing, learning memory and senses. Likewise, increased areas of blood flow to the area of the brain associated with food reward, very similar to the ‘foraging’ response we see in animals.

Further studies have explored the impact of high-glycemic diets and cognitive function and amyloid burden in humans. High glycemic diets were associated with greater amyloid deposition. Additionally, impaired fasting glycaemia was associated with increased amyloid burden in highly metabolic areas of the brain in cognitively ‘normal’ older adults

Fructose levels in patients with Alzheimer’s

Alzheimer’s is now listed with dementia (the umbrella term for diseases of cognitive decline) as the number one killer in the UK, it ranks lower down in other developed countries. This difference may be because we have the best healthcare system (NHS) in the world and people probably die of other diseases first in other countries. The scientific evidence highlights obesity, diabetes and excess alcohol intake as risk factors for Alzheimer’s. However, people who are slim also develop Alzheimer’s.

Alzheimer’s has recently been proposed as Type 3 diabetes, as evidence tells us it appears to be related to insulin resistance of the brain. Weight gain in mid-life is a risk factor for Alzheimer’s (ELSA study) and long term elevated uric acid is associated with cognitive decline.

Brain autopsies of people with Alzheimer’s have shown that levels of sorbitol and fructose are 3-5 times higher than people without Alzheimer’s. A recent paper by Professor Johnson and his team proposed the question of whether the ‘wandering’ or ‘walking about’ behaviour we see in Alzheimer’s could potentially be a ‘foraging’ response, thus supporting the view that they are indeed walking with a purpose.

Please read the paper by Johnson, Tolan and Bredeson et al, 2023 for more further detail on the proposed mechanism, it’s a fascinating read and it seems to bridge together the human evidence with the metabolic ‘survival’ switch shown in animals.

We have an epidemic of obesity and metabolic diseases

The rise of obesity and Type 2 diabetes has risen significantly in the 20th century, with a dramatic upturn in the late 1970’s. This correlates very nicely with the introduction of sugar, the refinement of whole grains and then the introduction of ultra processed foods in the 1970’s. 4.3 million in the UK have type 2 diabetes, with at least (estimated to be much higher) another 850,000 undiagnosed and a further 2.4million at risk (pre-diabetes). Diabetes now affects more than 1 in 10 worldwide. Data from the US suggests the incidence of both Type 1 and type 2 diabetes in 1880 was 2 in 100,000.

The Organisation for Economic Co-operation and Development (OECD) reports obesity rates in the UK are the highest in Europe with 1 in 3 men now overweight and 1 in 4 obese. UK rates have increased faster than other OECD countries and are expected to rise another 10% by 2030. Worldwide prevalence of fatty liver is estimated to be around 25% in adults. A recent study in the Lancet revealed a worrying prevalence of fatty liver in 1 in 4 young adults (aged 24 years). Prevalence of both obesity and type 2 diabetes is rising significantly in children in the UK and world wide, along with fatty liver, food allergies and attention deficit hyperactivity disorder (ADHD). ADHD is increasing amongst adults too, and it is associated with economic deprivation and recent studies suggest people with ADHD and their parents may have a higher risk of Alzheimer’s. A recent national Israeli birth cohort study which followed the cohort for just over 17 years found a 2.77 fold risk for Alzheimer’s in those with adult ADHD. A Swedish cohort study found a similar almost threefold risk.

The term ‘Metabolic’ means the chemical changes that happen in living cells to provide energy for vital processes and activities, and to incorporate new material. A syndrome is a collection of signs and symptoms that happen together and define a specific abnormality or condition.A person is usually defined as having metabolic syndrome when they have three or more of the following:

Obesity
Elevated blood triglycerides (a type of ‘bad’ cholesterol)
Low HDL (good) cholesterol
High blood pressure
Elevated blood sugar

The charity Heart UK estimate the prevalence of metabolic syndrome to be 1 in 4 in the UK. The trend of rising symptoms of obesity in children is extremely worrying. We may have a ticking time bomb ahead of us if we do not act now.

Weight appears to be a symptom of metabolic disease and not the cause

Obesity rarely presents on its own, it’s often accompanied by high blood pressure, high LDL and triglyceride cholesterol, low HDL cholesterol, insulin resistance, type 2 diabetes, respiratory, kidney and heart conditions and it is associated with a greater risk of other metabolic conditions including cancer and Alzheimers. Leptin resistance characterised by high levels of the hormone leptin and increased hunger is common amongst people with obesity. Studies in mice show you can induce obesity in previously lean mice when they are transplanted with the gut microbiome of an obese human. This is becoming an increasing area of interest, whereby clinical studies have shown favourable effects on metabolic syndrome, suggesting the gut may be a central driving component of obesity.

In studies in mice, youth is protective, owing to the ability of the mitochondria to repair. Additionally, calorie restriction and exercise help minimise mitochondrial damage, improve insulin resistance and mitigate weight gain (just like we see in humans) but neither of these interventions stop the mice getting metabolic syndrome. Could it be that we have focused our efforts on people who are obese, completely ignoring the TOFI’s (thin on the outside and fat on the inside). For some reason, we have just assumed that seemingly slim people must be healthy and eat well. How many times do we hear the phrase ‘I’m okay I can eat what I like and I don’t gain weight’. What if these people are just less genetically susceptible to weight gain. Additionally, the impact of long term calorie restriction is a concern. Females have a higher rate of osteoporosis and potentially caloric restriction and/or over exercising to control weight could play a part in this. Additionally, slim people are not immune from lots of these major metabolic disorders, so many of which are related to insulin resistance and the gut microbiome. The TOFI’s may be constantly or intermittently activating this switch, they may not gain weight like most people, they may be exercising more or restricting their intake in some way, thus their HbA1c (a marker used to diagnose pre-diabetes and diabetes) may not be raised. Both obesity and diabetes appear to be symptoms of metabolic syndrome rather than the cause of all these metabolic diseases.

An increasing number of metabolic conditions are now linked to insulin resistance…

An increasing number of conditions are now linked to insulin resistance. Here are just a few….

Type 2 diabetes
Type 1 diabetes
Polycystic ovarian syndrome (PCOS)
Alzheimers
Renal failure
Hypertension
COPD
Cancer

Anxiety
Depression
Attention deficit hyperactivity disorder (ADHD)
Long COVID
Asthma
Schizophrenia
Bi-polar disorder

MND
Parkinsons
IBS
Food allergies
Fibromyalgia
Acne
Alopecia
Osteoarthritis

The role of addiction

There is more and more evidence suggesting sugar and ultra processed foods may exert addictive behaviours in humans which result in a craving response in the brain, similar to the cravings seen in alcohol, cocaine and nicotine. These foods appear to cause a surge of dopamine in the brains of humans. Neurons do not like to be flooded with dopamine and it has been proposed they turn down their dopamine receptors as a protective mechanism to dampen the response. This then means people need a bigger hit of these foods to satisfy their cravings, increasing the addiction. Studies on humans have demonstrated altered blood flow responses in the human brain following a dose of intravenous fructose. Areas affected are similar to those seen in the ‘foraging’ type response (as outlined above). Studies suggest changes in the gut microbiome, particularly with low fibre diets, may alter the gut microbiome diversity over time and drive cravings for sugar and processed foods. It may be worth noting that alcohol can be metabolised via the polyol pathway in humans.

The Mediterranean diet and the pitfalls of the 7 countries study

The 7 Countries study was a collaborative effort by scientists (Ancel Keys et al) to help provide answers to the increasing prevalence of cardiovascular disease. In-depth analysis of diets of various cohorts of men across the world were done in the 1960’s and these cohorts were followed up 25 and 50 years later. Following the initial analysis the concept of a Mediterranean diet was born, which pieced together dietary and lifestyle themes across the 7 countries which appeared to lower cardiovascular disease. Contrary to popular belief, the French were reportedly invited to take part but chose not to. Additionally, the cohorts chosen were not necessarily representative of their country.

This 7 countries study was by no means perfect but it did bring to light the potential protective effects of plant based fats, vegetables, fibre and anti-oxidants and flavonoids, including an association of reduced depression and cognitive decline. 25 and 50 year follow ups highlighted the strong positive correlation of sucrose (sugar) and coronary heart disease deaths. It also highlighted that higher carbohydrate intake was associated with reduced coronary heart disease (CHD) deaths. However, the recent 60 year until extinction follow up study (May 2023) noted that although the US, Finland and Netherlands had higher incidence of CHD, associated with higher cholesterol, they noted an unexpected finding that Japan, Italy and Greece cohorts, with lower cholesterol, had a significantly higher incidence of stroke and heart disease of unknown aetiology. There was little difference in overall cardiovascular disease (CVD) across all countries and the rate of metabolic diseases have soared in all of these countries since the 1960’s. Greece the country with a high intake of plant based fats appeared to come out slightly better in terms of age at mortality.

In the original study it was noted that Japan consumed a lot of white rice, salt and very little fat but they also consumed a lot of legumes (pulses) and vegetables. Italy consumed some pasta but they also had a high intake of plant based fat and the highest intake of vegetables. Greece consumed some wholegrain bread but they also consumed a lot of grains, plant based fats, vegetables, fruits and legumes. Perhaps it is noteworthy that Japan appear to have an increasing prevalence of myopia (short sightedness which is related to oxidative stress in the mitochondria of the eye). This prevalence is markedly increasing amongst school children with an almost 95% prevalence shown in recent studies ( yes you did read that correctly almost 95%!). Additionally, there is reportedly a higher incidence of myopia across Asia, particularly in younger generations living in urbanised populations when compared to other westernised countries. Additional pitfalls of Seven Countries are that it looked only at men, cohorts did not necessarily represent typical diets of their country and it looked at one snap shot in time. For example, men were aged 40-59 when the initial dietary recall was collected, thus missing an important aspect of dietary intake in the years preceding this. After all, lifetime dietary intake appears to effect cardiovascular disease, rather than acute intake. As I mentioned above the Green Revolution in the 1940’s massively increased the global accessibility of refined grains such as bread and pasta.

Above image shows the increasing prevalence of myopia across East Asia. Reduced outdoor activity and increased screen time are associated with increased risk of myopia. However, this uptick occurred long before social media.

The theme which defined the ‘Mediterranean diet’ included:

Varying amounts of total fat
- Mainly olive oil
- Low in saturated fat
- Very low in trans-fats
Little red meat
Low in dairy – mainly from small amounts of cheese and yoghurt
Rich – in fibre predominantly unprocessed from whole grains and pulses (lentils, peas and beans)
Rich in anti-oxidants and flavonoids i.e. fruits and vegetables, cocoa and tea.
Moderate amounts of red wine (equivalent to around 125-150ml of today’s red wine – alcohol content has increased since the 1960’s)
Small amounts of dark chocolate

Somehow the above became translated into this….

There are few minimally processed foods on this guide and no minimally processed whole grains (unless you view the rice in a brown bag as wholegrain rice). They became replaced by boxed cereals and bagels. Additionally, it appears as thought the pulses became a token gesture to the vegetarians and vegans.

Additionally, the low fat message is outdated and not supported by the current evidence base.

Dietary fibre and links with Western metabolic diseases

There is an abundance of studies suggesting fibre appears to have beneficial effects on health, reducing the risk of diabetes, cancer, metabolic disease and Alzheimer’s. More recently multiple clinical studies link changes in the gut microbiome with metabolic diseases. However, studies on fibre supplementation provide mixed results. There is a suggestion that dose and fibre structure are important, with larger more intact and minimally processed grains appearing to be more beneficial.

In the 60’s and 70’s, Denis Burkitt, a surgeon who had been working in Africa, linked together ideas from a range of disciplines with observations from his experience of working in Africa to highlight the role of fibre in human health. Burkitt noticed that ‘Western’ diseases like obesity, cancer and bowel diseases were almost unheard of in developed countries. He noted the fibre intakes of people living in developing countries (who had not yet adopted the Western diet) were significantly greater than those seen in developed countries. Most Africans were consuming around 100g of fibre a day which was significantly greater than the fibre intakes in Western diets. Burkitt pulled together the work of three physicians (Peter Cleave, G. D. Campbell and Hugh Trowell), a surgeon (Neil Painter) and a biochemist (Alec Walker) to propose that diets which were low in fibre increased the risk of metabolic diseases, including CHD, obesity, diabetes, dental caries, various vascular disorders and large bowel conditions such as cancer, appendicitis and diverticulosis. They also noted low fibre diets associated with western diseases were always accompanied by increased intakes of added sugars and refined carbohydrate.

Average intakes of fibre in the UK today are believed to be less 15g per day, with the majority of this coming from refined sources of fibre. Recommended intakes of fibre in the UK are meagre 30g a day.

There is common theme amongst 1960’s Mediterranean diets and blue zones. They were:

Mainly plant based (with high quality meat, fish and/or dairy complimenting the diet in small amounts)
High in seasonally grown fresh vegetables and fruit
High in pulses – a daily intake, pulses were the staple source of protein
High in plant based fats, mainly from olive oil, nuts and seeds (with the exception of Japan)
High in minimally processed whole grains (with the exception of Japan), such as rye, barley and oats.

No medication gets to the mitochondria!

Mitochondria are essential for cellular metabolism and are involved in intracellular signalling, cell differentiation, morphogenesis (cell structure and development) and cell death. Mitochondrial dysfunction is a factor in the development of diabetes. It contributes to insulin resistance in the liver and skeletal muscles, as well as defects in insulin secretion by pancreatic β-cells. Unfortunately, there are currently no therapies available for type 2 diabetes that specifically target the preservation of mitochondrial function.

An increasing number of diseases are associated with problems in the functioning of mitochondria. These can be caused by genetic defects affecting core components of mitochondria or by disturbances in pathways that regulate mitochondrial balance. Because of this, mitochondria are considered a key focus in various conditions, including cancer, neurodegenerative diseases, and metabolic disorders.

References

Key papers

Richard J. Johnson, Dean R. Tolan, Dale Bredesen, Maria Nagel, Laura G. Sánchez-Lozada, Mehdi Fini, Scott Burtis, Miguel A. Lanaspa, David Perlmutter, Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism? The American Journal of Clinical Nutrition, Volume 117, Issue 3, 2023,Pages 455-466,ISSN 0002-9165

Johnson RJ, Stenvinkel P, Andrews P, Sánchez-Lozada LG, Nakagawa T, Gaucher E, Andres-Hernando A, Rodriguez-Iturbe B, Jimenez CR, Garcia G, Kang DH, Tolan DR, Lanaspa MA. Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts. J Intern Med. 2020 Mar;287(3):252-262.

Johnson RJ, Lanaspa MA, Sanchez-Lozada LG, Tolan D, Nakagawa T, Ishimoto T, Andres-Hernando A, Rodriguez-Iturbe B, Stenvinkel P. The fructose survival hypothesis for obesity. Philos Trans R Soc Lond B Biol Sci. 2023 Sep 11;378(1885):20220230.

History

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Food addiction

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Pharmacy and the mitochondria

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A Mediterrean diet

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