As I’ve discussed in previous articles (see Diabetes: ‘awareness’ vs action, Preventing bowel cancer, Keep your brain young with greens and Cancer prevention: myths, cons and big fat lies), I am deeply mistrustful of ‘awareness’ days, weeks and months.

All too often, they create a climate of helplessness around feared diseases, promote ineffective or unproven screening tests, and either underplay or outright ignore effective prevention methods that people can employ to dramatically reduce their risk not just of the disease that the ‘awareness’ campaign is focused on, but virtually all chronic degenerative diseases that plague Westernised populations. Even worse, they often promote fundraising activities centred on consumption of foods that increase the risk of the target disease!

Unfortunately, the ‘awareness’ campaigns promoted by both the US Prostate Cancer Foundation, and the Prostate Cancer Foundation of Australia, are by no means exceptions to this rule.

The major thrust of these campaigns is to promote screening for prostate cancer, via the prostate specific antigen (PSA) test. For example, the Prostate Cancer Foundation (PCF) flags September as the month in which it “highlights the importance of screening for the disease”...

... and its ‘Know Your Risk’ guide stresses that “Prostate cancer screening starts with a simple blood test”:

What exactly is that “simple blood test”? You have to do a bit more clicking around to confirm that, it is, of course, the PSA test:

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Likewise, in the promotional material for its September fundraising campaign, ‘The Long Run’, the Prostate Cancer Foundation of Australia (PCFA) highlights the case of a man whose prostate cancer was detected by “a routine blood test”:

What’s up with this caginess around naming that “routine” or “simple” blood test as a PSA test? Because as the PCFA knows damn well, “screening” or “routine” testing for prostate cancer - that is, running a PSA test on a man who does not have any relevant symptoms - is not advised by top cancer authorities - including the Cancer Council - due to a lack of evidence of substantial benefit, and evidence of substantial harm:

“Testing to assess whether an asymptomatic man may be at risk of developing prostate cancer, using the prostate specific antigen (PSA) blood test is common. The PSA test measures the amount of prostate specific antigen in blood, however, as the test is not cancer-specific, testing asymptomatic people using the PSA test is a complex and controversial issue and the subject of ongoing debate, both in Australia and internationally. The population health benefits of screening for prostate cancer using the PSA test are currently uncertain…

While some prostate cancers are aggressive and life-threatening, many grow slowly and do not progress sufficiently during a person’s lifetime to cause any problems. No current test, including the PSA test, can adequately distinguish between these two kinds of prostate cancer. Consequently, while testing of healthy people may offer a longer life to those with aggressive cancers, the consequences of a test may harm people with indolent cancers by exposing them to treatments that cause significant side effects such as urinary incontinence and sexual dysfunction without any compensating benefit.

While the uncertainty persists, current evidence does not support population screening for prostate cancer. Individuals who ask for, or are offered testing, are advised to make an informed decision about whether or not to be tested.”

Prostate Cancer: Executive summary

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The great cancer screening con

Cancer screening is the practice of using diagnostic tests on people who have no signs or symptoms of the cancer they’re being screened for, in an attempt to detect the cancer at an earlier, and hopefully more treatable, stage. Notice that both the PCF and PCFA refer to “catching” or “detecting” prostate cancer “early” as part of their sales pitch for screening:

Who wouldn’t want to catch their cancer early, so that they could be successfully treated and become a prostate cancer survivor, just like our happy chappy, the “fit, healthy” Bruce? (Doesn’t he just look like the very picture of fitness and health in that photo?) Problem is, as I discussed in Major study finds that cancer screening programs don’t extend life, you’re about as likely to have you life expectancy shortened by undergoing screening for prostate cancer using a PSA test, as you are to have it increased. How is that even possible? To understand why, you need a little background on both PSA, and the PSA test.

The PSA test measures the amount of prostate specific antigen, an enzyme produced solely by the prostate gland - hence its name, ‘prostate specific antigen’ - in the bloodstream. Both healthy prostate cells and cancerous prostate cells produce PSA, and in the majority of cases, elevated PSA is not due to prostate cancer, but to other conditions such as benign prostatic hyperplasia (non-cancerous enlargement of the prostate due to aging), inflammation of the prostate (prostatitis), and simply getting older. In addition, ejaculation and vigorous physical activity can temporarily raise PSA levels. But how many men are warned by their doctors to avoid intense exercise, sex and masturbation for at least 48 hours before their PSA test?

The scientist who discovered PSA back in 1970, Dr Richard Ablin, has for decades argued vociferously against using PSA testing for prostate cancer screening. He describes the promotion of PSA testing as “a public health disaster“ because of the enormous sums of money wasted on it, and the almost incalcuable harm done to men (and their families) through overdiagnosis and overtreatment. Dr Ablin decries “the continual proselytizing of fear” of a disease with a lifetime risk of death of only 2.5 per cent, describing PSA testing as a “cash cow” for urologists and other medical professionals who profit from patient’s progression “from PSA, to ultrasonography, to biopsy”, and then to radical prostatectomy and/or radiation therapy. You can watch an interview with Dr Ablin here.

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The US Preventative Services Task Force issued updated guidelines on screening for prostate cancer in 2018. After an exhaustive review of the published literature, they concluded the following:

• 1000 men aged 55 to 69 years must undergo periodic PSA screening for 13 years to prevent approximately 1.3 of them from dying of prostate cancer.

• If the same 1000 men are screened for the same duration, three cases of metastatic prostate cancer will also be prevented by catching the disease at an early stage.

• Men participating in PSA screening will not actually live any longer, even if the test detects their prostate cancer at an early stage and it is successfully treated.

• There is inadequate evidence to assess whether 55-69 year old men with a family history of prostate cancer may experience any different level of benefit from screening than the average-risk population.

• Men aged 70 years and older do not have a lower risk of dying of prostate cancer if they undergo PSA screening.

• Over the course of ten years of participating in PSA screening, over 15 per cent of men will have at least one false-positive test result (i.e. a rise in PSA, which raises the suspicion that they have prostate cancer). The diagnostic procedure used to investigate the cause of the raised PSA - biopsy of the prostate - include pain, blood in the semen, and infection. Approximately one per cent of men who undergo prostate biopsies will suffer complications that require hospitalisation. The false-positive and complication rates from biopsy are higher in older men.

• 20 to 50 per cent of men diagnosed with prostate cancer through PSA screening may be overdiagnosed - that is, diagnosed with a prostate cancer that would never have become symptomatic during their lifetime; they would have died with their prostate cancer rather than from it. Overdiagnosis rates rise with age and are highest in men aged 70 or older, because they are more likely to die of other causes before their prostate cancer becomes advanced enough to kill them.

• Overdiagnosis results in overtreatment - that is, treating prostate cancer in men who wouldn’t have died from it anyway. Overtreatment provides such men with no benefit, and substantial harms, including erectile dysfunction (two in three men who undergo surgical removal of their cancerous prostate gland [radical prostatectomy], and over half of men who receive radiation therapy, suffer long-term erectile dysfunction); urinary incontinence (roughly one in five men who undergo radical prostatectomy need to use incontinence pads), and troublesome bowel symptoms (up to one in six men who have radiation therapy experience long-term bowel symptoms including bowel urgency and faecal incontinence).

• Men aged 70 or older have a greater risk of harms from diagnostic biopsy, and harms from treatment.

The USPSTF also recommends against digital rectal examination (DRE) as a prostate cancer screening tool due to a lack of evidence of benefits.

In short, there is simply no evidence to support the inference of PCF and PCFA that undergoing screening will save men from dying of prostate cancer. So, should men just shrug their shoulders and leave it up to fate to decide whether they will or won’t succumb to prostate cancer? Hell, no. There is a wealth of evidence linking various diet and lifestyle factors to a heightened risk of prostate cancer:

• Dairy products: The Physicians’ Health Study, involving 21,660 male US physicians, found that men who consumed more than 2.5 servings of dairy products had a 12 per cent higher risk of developing prostate cancer than those who had less than half a serving per day. Higher intake of skim and low-fat milk intake increased the risk of low-grade, early stage, and screen-detected cancers; and men who consumed one serving per day of whole milk had a 49 per cent higher risk of fatal prostate cancer than men who rarely consumed it. Even worse, men who regularly drank whole milk were 2.17 times more likely to die of prostate cancer than those who rarely or never drank it. The Adventist Health Study–2 found that men in the 90th percentile of dairy product intake (average intake 430 g/day) had a 62 per cent higher risk of developing prostate cancer than men who never consumed dairy.

• Red and processed meat: A pooled analysis of 15 prospective cohort studies found an increased risk of advanced prostate cancer in men who ate more red meat - both fresh and unprocessed. A subsequent meta-analysis of 25 prospective studies confirmed the link, which was more evident for processed meat than for fresh red meat.

• Eggs: The same pooled analysis identified a 14 per cent higher risk of advanced and fatal prostate cancers in men who ate over 25 g of eggs (roughly half an egg) per day compared to those who ate less than 5 g per day. And in men already diagnosed with prostate cancer, those who ate the most eggs had twice the risk of recurrence or progression of their cancer.

• Oily fish: The Danish ‘Diet, Cancer and Health’ study, which tracked over 27 000 men for up to 20 years, found that the risk of dying of prostate cancer rose 27 per cent for each additional 25 g of fatty fish (e.g. salmon, tuna, sardines, mackerel, herring, kippers, eel, trout, mullet, trevally and snapper) eaten per day.

• Western diet pattern: Men who had been diagnosed with prostate cancer were over two and a half times more likely to die of that cancer in the subsequent ten years, and 67 per cent more likely to die of any cause, if their diet most closely adhered to “a Western pattern, characterized by higher intake of processed and red meats, high-fat dairy and refined grains”, then men following the least Western-type diet.

• Obesity: Obese men are more likely to have prostate cancer recurrence after initial diagnosis and treatment, to suffer more severe treatment-related adverse effects, to develop metastatic disease, and to die of their prostate cancer.

On the other hand, the following factors have been linked to a decreased risk of prostate cancer:

• Cruciferous vegetables: A 2012 meta-analysis found that intake of cruciferous vegetables such as broccoli, cabbage, kale and Brussels sprouts significantly decreased prostate cancer risk.

• Allium vegetables: A systematic literature search identified nine studies involving over 130 000 participants which found that regular intake of allium vegetables - especially garlic - significantly decreased the risk of prostate cancer. Other members of the allium family include onions, leeks, shallots and chives.

• Physical activity: Regular exercise decreases the risk of prostate cancer, especially advanced cases.

And in men already diagnosed with prostate cancer, Dr Dean Ornish showed that a comprehensive lifestyle program incorporating low-fat plant-based diet, moderate exercise, stress reduction and group support could prevent progression of early-stage prostate cancer, thus saving men from the need for surgery, radiation therapy and androgen deprivation, and reduce PSA (which is actually a good metric for monitoring men with prostate cancer).

Sadly, not in over 30 years of clinical practice have I seen a client whose GP or urologist told him what he could do to reduce his risk of prostate cancer. And nowhere on PCF’s or PCFA’s websites are prevention strategies discussed; their fundraising is exclusively aimed at developing improved diagnostic and treatment options, rather than saving men from the trauma of a prostate cancer diagnosis in the first place.

All in all, Prostate Cancer Awareness Month is yet another missed opportunity to educate the public on how to take responsibility for their own health and implement simple lifestyle changes that not only reduce the risk of this one disease, but improve overall well-being and quality of life.

I can’t think of one good rationale for encouraging men to ‘raise their awareness’ of prostate cancer in September, or any other month, unless that awareness-raising is directed toward a) finding a health professional who is well-informed enough to talk them through the risks and benefits of prostate cancer screening (or screening for any other type of cancer, for that matter) and b) helping them to develop a plan to minimise their personal risk of developing prostate cancer.

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But the human-microbiome interaction doesn’t just impact on you. If you’re a woman who is pregnant, or planning to become a mother, you need to know that the diet that you eat before and during conception also has a profound and long-lasting impact on the gut microbiome of your baby.

To be specific, women who eat a high fat diet before and during pregnancy may be causing alterations in their developing babies’ microbiome that predispose their infants to diabetes and obesity, regardless of whether they themselves become overweight on this diet.

Until relatively recently, it was believed that babies were born sterile - in other words, that their first contact with bacteria was at birth. However, we now know that the placenta (the organ that develops in a woman’s uterus during pregnancy, ‘housing’ the baby throughout pregnancy and providing oxygen and nutrients to fuel its growth) has its own microbiome. And, since meconium - the newborn’s first bowel movement, which is composed of substances ingested while the baby was still in its mother’s uterus - contains microbes, it is clear that those microorganisms are transferred from the placenta, via the amniotic fluid in which the foetus floats, to the developing foetus.

Researchers now believe that the placental and amniotic fluid microbiomes ‘seed’ the developing foetus with its first microbes, preparing it for the more intensive colonisation that occurs during birth and breastfeeding.

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Although the placental microbiome is unique, it bears the greatest resemblance to the mother’s oral microbiome - the colonies of bacteria that inhabit the mouth and throat - and has somewhat less in common with the maternal gut microbial profile.

How do bacteria from the mouth and gut set up shop in the placenta? Oral bacteria can enter the bloodstream, especially if the gums are inflamed (as is common during pregnancy due to hormonal and vascular changes), and travel to the placenta to colonise it. The gut membrane is also ‘leakier’ during pregnancy, allowing what is called translocation of bacteria from the gut lumen (the ‘space’ inside the gut) into the bloodstream.

In addition, specialised white blood cells known as mononuclear cells have been found to transport gut bacteria to the mother’s mesenteric lymph nodes (the tissues that receive lymph drained from the small intestine and colon) and mammary gland in late pregnancy and during lactation in mice. There is strong evidence that the same process occurs in humans too. So bacteria may travel to the placenta under their own steam, or be intentionally delivered there by the mother’s immune system.

Incidentally, the discovery that oral microbiota can colonise the placenta may help to explain the long-observed association between periodontal disease in pregnant women and an increased risk of premature birth. Periodontal disease is essentially a dysbiotic condition, in which the oral microbiome becomes unbalanced and dominated by disease-causing organisms.

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The placental microbiome and maternal and infant health

The placental microbiome changes throughout the stages of pregnancy. It becomes less diverse but more unique to each individual as pregnancy progresses, hinting that a pregnant woman’s diet, lifestyle and other environmental factors may shape the bacterial ecosystem within her placenta - with profound implications for her developing foetus.

For example, there are significant differences in the placental microbiome of women who develop gestational diabetes mellitus (GDM). GDM is a type of diabetes resulting from severe insulin resistance that begins during pregnancy and resolves as soon as the woman gives birth, but leaves both her and her baby at increased risk of developing type 2 diabetes later in life.

The placental microbiome of women with GDM harbours more Proteobacteria and Alistipes and fewer Firmicutes than non-GDM placentas. Proteobacteria are a bacterial phylum that includes many human pathogens, including Bordetella (the cause of whooping cough), Neisseria (gonorrhea and meningitis), Escherichia, Shigella and Salmonella (food poisoning), Yersinia (gastroenteritis, plague), and Helicobacter (gastritis, stomach ulcers). Alistipes is a ‘bilophilic’ or bile-loving genus in the Bacteroidetes phylum.

Both Proteobacteria and Alistipes are known to multiply rapidly in the gut microbiome of people who adopt a diet comprised entirely of animal products. People who eat a typical Western diet (high in fat and refined carbohydrates, and low in fibre) also have higher Proteobacteria and Alistipes abundance. On the other hand, Firmicutes metabolise the carbohydrates in plants that are indigestible to humans: fibre, resistant starch, and non-starch polysaccharides. Consequently, Firmicutes numbers drop on a low-carbohydrate, animal-based diet.

Another example: Women who are overweight when they become pregnant have more Bacteroides and Staphylococcus in their gut microbiota than normal-weight pregnant women. And higher Bacteroides concentrations were associated with excessive weight gain over the course of pregnancy - regardless of whether women begin or end their pregnancy obese. Bacteroides are bile-tolerant bacteria whose counts increase in people eating high-fat, high-protein animal food-based diets. The altered placental microbiome seen in women with excessive gestational weight gain is associated with an increased risk of premature birth.

How might maternal obesity and excessive gestational weight gain affect the placental microbiome? Whereas oral and gut microbes primarily metabolise carbohydrates and amino acids as their fuel source, placental bacteria specialise in metabolising fats. Researchers have proposed that

“The placental microbiota may aid in efficient extraction of energy from circulating fatty acids and play a crucial role in supplying energy-yielding substrates to the fetus.”

Contributions of the maternal oral and gut microbiome to placental microbial colonization in overweight and obese pregnant women

An increased efficiency at extracting energy from fat and delivering it to the foetus is highly adaptive for pregnant women faced with food shortage. Unfortunately, in the modern environment, dietary fat is all too easy to obtain.

Fat chance of having a healthy pregnancy

The link between high-fat diets and disease-promoting changes in the placental microbiome was first explored in animal studies.

When female mice were fed a high fat diet (45 per cent of calories from fat) from eight weeks before they became pregnant, and continuing throughout gestation, their gut microbiomes were significantly different from those of mice who were fed standard lab chow (17 per cent calories from fat) before and during pregnancy. Specifically, the animals’ gut microbiota overexpressed genes involved in the metabolism of fatty acids and ketone bodies, the breakdown of glucose (glycolysis), and the formation of glucose from fats and amino acids (gluconeogenesis). In other words, the gut microbiota of mice fed a high fat diet before and during pregnancy became significantly more efficient at harvesting energy from food.

Similarly worrying outcomes were observed in Japanese macaques, primates whose normal gut microbiota is more similar to that of humans than that of mice. Female macaques who were fed a high fat diet (36 per cent fat from animal fat, fish oil and corn oil) before and during pregnancy, developed a dysbiotic gut microbiome, which was ‘inherited’ by their offspring. Even when the baby macaques were switched to a low fat diet after weaning, the maternal high fat diet-induced dysbiosis was not fully corrected.

Animals who were fed the low fat diet (13 per cent fat from soy bean oil, but the same number of total calories as the high fat diet) all tended to remain lean throughout the experiment whereas roughly two thirds of the macaques fed the high fat diet became obese and insulin resistant, and the remaining one third stayed lean and insulin sensitive.

However, all macaques fed a high fat diet showed similar changes in their gut microbiome, regardless of whether they were obese or lean, and all high fat-fed macaque mothers ‘passed on’ their dysbiotic gut microbiome to their infants. The researchers concluded

“Our data demonstrat[e] a role for the maternal diet, rather than maternal obesity per se, in shaping the offspring gut microbiome at 1 year of age.”

High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model

So, a high-fat diet during pregnancy causes adverse and heritable gut microbiome changes in mice and monkeys... but what about men (or more to the point, women1)?

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In a study of overweight women in early pregnancy, higher fibre intake was associated with greater gut microbiota richness and reduced levels of a low-grade inflammation marker, GlycA. Conversely, higher intakes of total fat, saturated fat, monounsaturated fat and omega-6 fat were all associated with decreased microbiota richness, with saturated fat exerting a particularly harmful effect. Women whose diet was both low in fibre and high in fat had increased representation of Bacteroidaceae family bacteria in their gut microbiota, and elevated levels of the inflammation marker GlycA.

Stool samples collected from newborn babies born to women who had eaten a high-fat diet during pregnancy (averaging 43 per cent of daily calories from fat) revealed a gut microbiome that was significantly different from babies of women whose fat intake was closer to population averages, and this altered gut microbiome was still apparent in stool samples collected six weeks after birth. As with the macaques, these distinct changes in infant gut microbiome occurred whether their mothers were obese or not.

And infants born to obese mothers had reduced microbial diversity and enrichment of fat-synthesising pathways in their gut microbiota metabolic profiles, peaking at three months of age and persisting until the final follow-up at six months of age. The gut microbiomes of obese children show increased metabolic activity, essentially extracting maximal calories out of the food eaten by their young hosts.

In summary, both the mother’s diet, and her body weight and composition, exert a profound and lasting influence on her children’s gut microbiota. Either having excessive body fat, or eating a high fat diet before and during pregnancy (regardless of whether or not it makes the mother herself fat) may set children up for a lifetime of struggling with their weight. On the other hand, diets rich in fibre and relatively low in fat - that is, wholefood diets high in unprocessed and minimally processed plant foods - make maternal weight management much easier, and also transmit a core microbiome that helps to protect children against metabolic dysfunction and obesity.

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For some time, researchers have investigated ‘the gut-brain axis’:

“a bidirectional communication network that monitors and integrates gut functions and link them to cognitive and emotional centres of the brain.”

However,

“Given mounting evidence that the microbiome has a key role in influencing the development and function of the nervous system through its interaction with the gut-brain axis, it has been suggested that a ‘microbiome-gut-brain axis’ may be a more appropriate model.”

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

Our growing understanding of this ongoing conversation between our brains and our gut microbiota holds enormous promise for developing new approaches to widespread psychological problems, given the evidence that there is a common gut microbial signature in both anxiety and depression - namely, “a reduction in anti-inflammatory, butyrate-producing genera (e.g., Faecalibacterium and Coprococcus) and increased pro-inflammatory genera (e.g., Eggerthella)”.

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A gut-centred approach to psychological distress focuses on shifting the composition of the gut microbiota toward a predominance of bugs that produce anti-inflammatory byproducts, thus suppressing the growth of their pro-inflammatory competitors. Changing your diet is by far the most powerful lever to pull, to achieve such a shift. Specifically, after analysing over 10,000 human microbiome specimens from people all over the world, along with responses to detailed diet, lifestyle and medical history questionnaires, the American Gut Project identified consumption of more than 30 different plant foods per week as the single strongest predictor of having healthy diversity in one’s gut microbiome. This same eating pattern - a wholefood diet centred on fibre-rich plant foods - was also associated with having greater abundance of Faecalibacterium prausnitzii and of another anti-inflammatory butyrate-producer, Oscillospira.

Exercise, and exposure to environments with rich microbial diversity via gardening and spending more time in nature, also boost healthy microbial diversity. And these lifestyle strategies can be augmented by supplementation with fermented foods, carefully-chosen prebiotics (substances that selectively feed desirable bacteria) and probiotic strains of bacteria.

It’s no great surprise that when people slash or even eliminate their intake of refined carbohydrates, junk fats and fried foods, and animal products, and replace them with a diverse array of whole or minimally processed fruits, vegetables, whole grains, legumes, nuts and seeds, herbs and spices, they experience better mental function and emotional stability. I’ve set hundreds of clients the ‘eat 30 different plants per week for a month’ challenge since the American Gut Project finding was published in 2018. The vast majority of them notice significant improvements in their psychological functioning, conveyed in terms such as

“I just feel better!”

“I feel lighter, somehow.”

“My brain fog has cleared.”

Antibiotics and mental health

Of course, we also need to be aware of the potential impact of common medical practices on the gut-brain axis. As I discussed in Drugs and gut bugs, nearly one quarter of drugs on the market today have been found to inhibit the growth of at least one strain of bacteria that forms part of our gut microbiota. The impact of such disruptions to the complex ecosystem of the gut has simply not been studied at this stage.

What is known, however, is that certain antibiotics, which exert major effects on the gut microbiome, can affect psychological functioning in profound ways, including:

1. Antibiotic-induced psychosis

Psychosis is a mental disorder in which a person loses the ability to distinguish what’s real from what isn’t. During a psychotic episode, a person may experience hallucinations (seeing or hearing things that aren’t there) and delusions (believing things that aren’t true), as well as confused or slowed thinking.

There are many case reports of antibiotic-induced psychosis in the medical literature. A 2014 systematic review of case reports of antibiotic-associated psychosis during treatment of urinary tract infections found that three different classes of antibiotics - fluoroquinolones, penicillins, and trimethoprim-sulfamethoxazole - had been reported to trigger psychosis within one week of commencing treatment. After ceasing the antibiotic, the psychosis resolved, again within a week. In some cases, doctors ‘rechallenged’ by administering the antibiotic again to patients after they had recovered from psychosis, and they relapsed back into psychosis.

One mechanism that has been proposed to explain antibiotic-induced psychosis is a sharp drop in levels of d-alanine, an amino acid that is produced by gut bacteria (as well as being supplied by the diet). Alanine binds to N-methyl-D-aspartate (NMDA) receptors in the brain. Underfunction of these receptors has previously been linked to symptoms of schizophrenia, which is a form of psychotic disorder; and drugs that block the activity of NMDA receptors, including ketamine and phencyclidine, are known to be capable of inducing psychosis.

According to this theory, antibiotic-induced psychosis is triggered when antibiotics cause depletion of d-alanine-producing intestinal flora, resulting in less d-alanine in the brain, and hence reduced stimulation of NMDA receptors.

Another potential contributing factor to antibiotic-induced psychosis is inflammation induced by the dysbiosis (imbalance in gut bacteria) that results from antibiotic treatment.

Antibiotic treatment is known to favour the proliferation of the Bacteroides family of bacteria, which harbour many antibiotic resistance genes and therefore tend to become dominant when antibiotics wipe out less resistant members of our gut microbial community - including beneficial genera such as Lactobacilli, Bifidobacteria, Akkermansia and Faecalibacteria.

Bacteroides, along with other gram negative bacteria, secrete pro-inflammatory neurotoxins including a substance known as surface lipopolysaccharide (LPS), which triggers an inflammatory response by our immune system. Many studies have reported higher inflammatory markers in schizophrenia patients as well as lipopolysaccharide binding protein, which is produced by the immune system to neutralise LPS, in people with schizophrenia.

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2. Antibiotic-induced anxiety and panic

A large population study conducted in the UK found that a single course of antibiotics raised the risk of developing anxiety, with risk rising higher with each course of antibiotics. Penicillins and sulfonamides were the biggest culprits; a single course of penicillin was associated with a 17 per cent higher odds of developing anxiety, while people who had taken more than five courses of penicillin had 44 per cent higher odds of anxiety.

Antifungal drugs were also found to increase the risk of anxiety, but their effect was less pronounced than antibiotics.

3. Antibiotic-induced major depression

The same UK study found that the risk of depression was also increased by a single course of any type of antibiotic. Penicillin was found to raise the odds by 23 per cent, and quinolones by 25 per cent. As with anxiety, the risk increased with each subsequent round of antibiotic treatment: two to five courses of penicillin led to 40 per cent higher odds of developing depression, and more than five courses raised the odds by 56 per cent.

Again, as with anxiety, antifungal drugs slightly raised the risk of developing depression.

As with psychosis, one mechanism by which antibiotics cause depression may involve LPS, which is overproduced as a consequence of antibiotic-induced dysbiosis. Our immune systems respond to the presence of LPS by producing antibodies. Levels of serum antibodies against lipopolysaccharide have been found to be higher in patients suffering from major depressive disorder (MDD) than in non-depressed people.

Given the well-documented role that antibiotics play in inducing both common psychological problems and severe mental disorders, and the increasing prevalence of these issues - including in children and adolescents - doctors need to be much more discerning in their prescription habits, and members of the public must become better informed about the risks of antibiotics.

Some examples:

1. Most cases of childhood middle ear infections do not require antibiotics, but parents still tend to pressure doctors to prescribe them, and unfortunately many doctors continue to do so (with or without parental pressure) even when they know there is little chance of the child benefiting from antibiotic treatment, as well as a significant risk of harm.

2. Antibiotics should not be routinely prescribed for sinus infections, as the harms clearly outweigh the benefits. A Cochrane review concluded that conclude that “there is no place for antibiotics for people with uncomplicated acute rhinosinusitis”. The Cochrane reviewers found that
   “Antibiotics may slightly shorten the time to cure, but only 5 (diagnosis based on symptoms, range 1 to 10) to 11 (diagnosis confirmed by x‐ray, range 1 to 21) more participants per 100 would achieve cure faster by taking antibiotics instead of placebo. When a fluid level or total opacification was present on computed tomography (CT), 28 more participants per 100 (range 7 to 53) achieved cure faster with antibiotics. Antibiotics do not reduce the time to pain relief or the general feeling of illness. People who take antibiotics do not resume daily activities earlier and do not take less analgesics or nasal decongestants than people treated with placebo. In people with purulent rhinorrhoea, 10 more people per 100 (range 3 to 17) would experience a faster resolution of nasal discharge by taking antibiotics. However, we found that 13 more people per 100 (range 9 to 18) would experience side effects of the treatment.”

3. Between 25 and 42 per cent of uncomplicated urinary tract infections (UTIs) in women resolve spontaneously, without any treatment at all. For women at low risk of complications of a UTI, home remedies accompanied by watchful waiting for signs of complications (which include increased frequency and urgency of urination; pain or burning when urinating; low grade fever; pressure or cramping in the lower abdomen and groin; cloudy, murky, or bloody urine; and a change in the odour of urine) is a viable option to avoid both the risks of adverse reactions to antibiotics, and the development of antibiotic-resistant strains of bacteria which may render antibiotics useless when they are truly needed.

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As a health practitioner, I’m seeing an increasing number of clients, from childhood upward, who suffer from psychological difficulties - especially anxiety and depression. All of them have a history of insults to their gut microbiome, with overuse of antibiotics featuring in many of their medical histories.

It takes a lot of work to restore a damaged gut microbiome to health. Most people respond well to dietary change, exercise, stress reduction, prebiotics, and targeted probiotics. But in some cases, it may not be possible to fully rehabilitate the gut.

The bottom line is that we need to see ourselves as custodians of our gut microbiome - and health and medical practitioners need to see themselves as custodians of their patients’ or clients’ gut microbiomes. Hippocrates’ maxim, “Firstly, do no harm” has never been more relevant than today, as both our understanding of the importance of the teeming communities of bacteria that inhabit our bodies, including our guts, increases, and the number of treatments that can harmfully alter those communities expands.

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To view the sources (links to articles, graphs, images and videos) that I referenced in this article, please visit the text version of this post:

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Parenthetically, the scene in American Beauty when Kevin Spacey voices perennial loser Lester Burnham’s ‘why’ for wanting to get in shape, is, for my money, one of the funniest moments in cinema1:

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For people with a weight loss goal, answering the ‘why’ question is incredibly important, because as sure as night follows day, anyone who is trying to lose serious weight is going to face equally serious obstacles. Lots of them. You don’t become obese by eating an extra bag of chips every now and again. Excessive body fatness is the result of years - and often decades - of unhealthy eating habits and sedentary lifestyle practices.

Overcoming these deeply-ingrained patterns, and rewiring one’s brain to consistently choose healthy food and regular physical activity, is not something that anyone achieves quickly. It takes diligent and protracted effort, willingness to endure suffering in service of a distant goal, and the emotional and cognitive ability to bounce back from inevitable setbacks. If you haven’t got crystal-clear on why you want to do this hard thing, you have roughly a snowball’s chance in hell of success.

So, why do you want to lose weight?

When I walk clients through the ‘seven levels of why’ exercise2 to elicit their motivations for losing weight, two ‘whys’ that almost always come up are, ‘because I want to have more energy’ and ‘because I want better quality of life’. The precise wording used to express these sentiments varies between people, but the underlying meaning is the same: ‘Carrying around all this extra fat is making me feel tired all the time, and generally making my life suck. I expect big improvements in both these domains, from shedding that fat.’

And they’re right to expect those improvements. People who lose weight by adopting healthy eating habits and regular physical activity pretty much always report that they have more energy and better quality of life as a consequence.

So you would think that any proposed weight loss intervention would be required to clear this bar before being approved by authorities and promoted by doctors: as a result of using the intervention, people should not only weigh less, but also have less fatigue and better quality of life. Honestly, it’s not that high of a bar, is it?

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But according to a systematic review and network meta-analysis published last month in the BMJ, not a single one of the top ten weight loss drugs currently on the market meaningfully improves quality of life, and none of them reduce fatigue while several of the most popular ones increase it. These drugs do, on the whole, cause people to lose weight. But what’s the point, if you lose that weight but still feel just as crappy as you did before - or, as is quite likely, even crappier?

The article includes a visual abstract which neatly sums up its primary findings:

Let’s unpack this graphic, fleshing it out with extra details from the text. The authors pulled 262 studies enrolling a total of nearly 100,000 overweight or obese adults, that reported randomised controlled trials (RCTs) of at least 12 weeks’ duration, which compared weight loss drugs with other weight loss drugs, or with lifestyle modification, or placebo. RCTs fulfulling these criteria were available for 19 weight loss drugs. Most of these drugs have not been trialled head-to-head against each other, making it difficult to directly compare both their efficacy and their side-effect profiles. This prompted the authors to perform a network meta-analysis:

“Network meta-analysis enables simultaneous comparison of several interventions, including those not directly compared in trials.”

Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis

The table below, summarising findings on benefits and harms, is busy but worth spending a few minutes to examine closely:

Ten of these 19 drugs were assessed as having either low to very low certainty evidence or moderate to high certainty evidence, of intermediate to high effectiveness at producing weight loss. (Certainty of evidence is assessed using the GRADE methodology, which takes into account factors like study design, risk of bias, inconsistency of outcome across different studies, publication bias, magnitude of effect and dose-response gradient.)

These ten possibly or probably effective weight loss drugs were:

• Tirzepatide (Zepbound, Mounjaro) - a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist

• Cagrilinitide + semaglutide (CagriSema) - an amylin-analog combined with a GLP-1 receptor agonist

• Ecnoglutide (Xianyida) - a novel cyclic adenosine monophosphate (cAMP)-biased GLP-1 receptor agonist

• Mazdutide - a GLP-1 and glucagon receptor dual agonist

• Retatrutide - a triple agonist of GIP, GLP-1 and glucagon receptors

• Oral semaglutide (Rybelsus) - a GLP-1 receptor agonist

• Survodutide - a glucagon receptor–GLP-1 receptor dual agonist

• Orforglipron (Foundayo) - a small-molecule, nonpeptide oral GLP-1 receptor agonist

• Subcutaneous [i.e. injected] semaglutide (Wegovy, Ozempic) - a GLP-1 receptor agonist

• Phentermine-topiramate (Qsymia) - an amphetamine-like stimulant and appetite suppressant combined with an anticonvulsant.

So, basically, nine drugs that monkey around with hormones that regulate gut function and appetite, and a weird-ass combo of a speed-like drug with an epilepsy medication. What could possibly go wrong? Quite a lot, actually.

Firstly, as the authors of the study point out, the drugs that cause the most weight loss are also the ones that cause the most side-effects (especially, but not limited to, gastrointestinal side-effects including gall bladder disorders), and the highest rate of discontinuation due to intolerable side-effects.

Secondly, none of these drugs improve quality of life to any meaningful degree; the minimally important difference on the quality of life scale employed in this analysis was ten points, and no drug exceeded a five point improvement.

Thirdly, of the top ten drugs for which data were available, all of them increased the risk of fatigue in comparison to lifestyle modification, even though they were more effective at causing weight and fat loss than lifestyle modification.

Fourthly, the drugs that cause the largest reductions in body weight and fat mass, also tend to reduce lean mass the most. As I discussed in GLP-1 agonist weight loss drugs: Leaning the ladder against the wrong wall, losing weight always means losing lean mass as well as fat mass, because moving a heavier body around requires larger muscles and denser bones than moving a lighter body. However, as you can see from the table above, for all the drugs for which data were available, the percentage of lean mass lost was greater in people taking weight loss drugs than in people undertaking lifestyle modification.

Think about these outcomes for a moment. Would you expect an obese person who lost weight to feel better - more energetic, fewer troublesome symptoms, improved quality of life, healthier body composition - assuming that the weight was lost intentionally, through diet and lifestyle modification rather than unintentionally, through illness? Of course you would. And a program that helped them to lose more weight would rationally be anticipated to help them feel more healthy.

But with drugs, it’s just the opposite - the greater the effectiveness at achieving the desired outcome of weight loss, the larger the burden of adverse effects. If you’ve read my previous article, Stop calling them ‘side effects’, you won’t be in the least bit surprised by this. As I wrote in that post,

“There are no ‘side-effects’ of drugs. Every change that a drug causes is an effect. Some of those effects are desirable to doctor and patient; some are undesirable, but all result from interference with human physiology.

Many drugs block enzymes. For example, angiotensin converting enzyme (ACE) inhibitors force blood pressure down by interfering with the enzyme that activates angiotensin, a blood vessel-constricting hormone. But ACE also breaks down a substance called bradykinin. When ACE’s activity is blocked, bradykinin levels build up, causing a chronic dry cough and hyperalgaesia, an abnormally heightened sensitivity to pain.

Statins inhibit the activity of HMG-CoA reductase, an enzyme that produces cholesterol. But HMG-CoA reductase also catalyses the synthesis of other biologically significant molecules, such as coenzyme Q10, which is necessary for energy production within mitochondria.

Other drugs impede the breakdown and removal of biochemicals. For example, selective serotonin reuptake inhibitors (SSRIs) increase the amount of serotonin in the synaptic cleft (the tiny gap between adjacent neurons) by blocking the reabsorption of this crucial communication chemical by the neuron that released it. But as well as impacting mood (not necessarily for the better), the interference with serotonin metabolism caused by SSRIs also suppresses rapid eye movement sleep, and impedes genital arousal in women and erectile function in men.

Still other drugs simulate the activity of biochemicals. GLP-1 receptor agonists such as Wegovy and Ozempic, which were developed as diabetes treatments but are now being hyped as miracle weight loss drugs, mimic the naturally occurring hormone glucagon-like peptide-1. GLP-1 stimulates the release of insulin by the pancreas, helping to reduce blood glucose levels, and turns off hunger signals in the brain. But it also slows down the emptying of food from the stomach into the small intestine. When GLP-1 release is overstimulated, a distressing condition called gastroparesis – paralysis of the stomach – can occur, resulting in bloating, vomiting, heart burn, abdominal pain, and diarrhoea. GLP-1 agonists also dramatically raise the risk of bowel obstruction and pancreatitis, both potentially life-threatening conditions.

If you’re thinking, ‘Wow, having abnormally heightened pain sensitivity, sexual dysfunction and pancreatitis doesn’t sound terribly healthy to me’, you’re damn right. I would argue that interfering with biological functions – which is what virtually all pharmaceuticals do – is, by definition, inimical to health.”

Stop calling them ‘side effects’

Let’s be very clear about this. People who lose weight through healthy eating and regular physical activity have more energy and better quality of life because they are healthier than they were before. People who take drugs to lose weight have better biomarkers, but they aren’t actually healthier - at least not in any sense that regular people would understand that word to mean.

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Why your ‘why’ matters

Every week I speak to clients who report that virtually every woman they know is using a weight loss drug of some kind. Many of them feel pressure to jump on board the GLP-1 train themselves, because they see their friends and colleagues shedding kilograms seemingly overnight, while their own rate of weight loss from making diet and lifestyle changes is much slower.

But you’re stuck with taking these drugs forever unless you want all the lost weight to pile back on:

“Weight regain after discontinuation of pharmacotherapy is substantial.43 A systematic review of 37 studies found that participants regained weight at an average rate of about 0.4 kg per month after stopping treatment, with a projected return to baseline weight within approximately 1.7 years, accompanied by loss of cardiometabolic improvements.43 Therefore, on the whole, benefits do not appear to be sustained without continued treatment, highlighting the importance of long term adherence, tolerability, and ongoing clinical support.”

Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis

And while you’re taking these drugs, you’re not actually going to reap some of the key benefits that you expect from losing weight, such as higher quality of life and better energy levels. That’s why clarifying your ‘why’ matters, when you’re setting an intention to lose weight. If your only ‘why’ is, ‘because I want to fit into a smaller clothing size’, then maybe drugs really are your best option, provided you’re prepared to shell out for them for the rest of your life. But if you actually want to feel better than you did when you were shopping in the plus-size department, putting in the hard work required to change your diet and lifestyle is your best bet.

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For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine.

To view the sources (links to articles, graphs, images and videos) that I referenced in this article, please visit the text version of this post:

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For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine.

“Against stupidity we are defenseless. Neither protests nor the use of force accomplish anything here; reasons fall on deaf ears; facts that contradict one’s prejudgment simply need not be believed – in such moments the stupid person even becomes critical – and when facts are irrefutable they are just pushed aside as inconsequential, as incidental. In all this the stupid person, in contrast to the malicious one, is utterly self-satisfied and, being easily irritated, becomes dangerous by going on the attack.”

Dietrich Bonhoeffer, from ‘After Ten Years’ in Letters and Papers from Prison

The belief that healthy eating is synonymous with ‘getting more protein’ is one of these stupid majority-held views. I’ve debunked the most popular myths about protein in previous articles, but the protein zombie just won’t die. Indeed, despite the fact that “the United States consumes more protein and more animal-based protein than most, if not all, countries in the world”, an astounding 61 percent of surveyed Americans reported intentionally increasing their protein intake in 2024, compared to 48 per cent who did so in 2019.

According to Cargill, the US-based multinational food corporation that commissioned the survey,

“Consumers increasingly view protein as essential for mental focus, emotional well-being and longevity.”

The Protein Profile: The 2025 Primer for Protein Trends and Tips

And furthermore, these protein-conscious consumers overwhelmingly prefer animal-sourced protein-rich foods, with 74 per cent of surveyed individuals endorsing the statement, “Eating meat is an important part of my diet” and more than 75 per cent indicating that they typically include animal protein in their evening meals.

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So, to sum up, despite already eating more protein than any other human population on earth, the majority of Americans are intentionally increasing their protein intake - especially their animal protein intake - because they believe that doing so will enhance their psychological well-being and longevity. And the evidence supporting this belief is... Nada. Big fat nothing. Giant goose-egg. Zip, zero and zilch.

In fact, the evidence points in exactly the opposite direction, as a review published on 31 July 2026 in Cell Press Blue documents, in exhaustive detail. But hey, who needs evidence to support their passionately-held belief, amirite?

I hope that I’m correct in assuming that if you read my articles, you are interested in evidence. So let’s unpack that recently-published review, which is titled ‘The hallmarks of protein and amino acid restriction in aging and longevity’. It summarises over 350 studies spanning almost a century of research, which collectively indicate that reducing either the total intake of dietary protein, or of particular amino acids, extends lifespan and healthspan in a wide range of organisms including yeast, fruit flies, rodents, non-human primates and human beings.

Of course, research conducted in non-human animals is both ethically dubious, and of questionable relevance to human health. In the field of longevity research, animal studies are conducted to identify metabolic pathways that affect end-organ function and lifespan - parameters that are difficult to study in living human beings, unless you’re a Dr Mengele wannabe. It turns out, though, that these metabolic pathways are common to pretty much every animal species studied (as well as yeasts), indicating that they’re evolutionarily conserved. That is, they’re governed by genes that have “remained essentially unchanged throughout evolution”, because they are unique and essential to life. Chief among these pathways is...

FGF21: The key metabolic driver of protein restriction’s many benefits

Fibroblast growth factor 21 (FGF21) is a hormone secreted in response to prolonged fasting and other forms of nutritional stress, including protein restriction. In research conducted in laboratory animals and/or in humans, FGF21 has been shown to:

• Reduce body weight in spite of increased food intake;

• Increase energy expenditure (i.e. increased metabolic rate), by

  • Partially turning fat-storing white adipose tissue into fat-burning brown adipose tissue (dubbed ‘beiging’) and

  • Ramping up heat-generating fat-burning in brown adipose tissue;

• Reduce circulating triglyceride (blood fat) levels by increasing their use by fat-burning cells, and decreasing their production in the liver;

• Increase insulin sensitivity;

• Reduce cell senescence (loss of a cell’s capacity to divide; accumulation of senescent cells is a hallmark of biological aging) and hence tamp down inflammation; and

• Extend lifespan.

In summary, protein restriction - just like prolonged fasting - induces FGF21 secretion, which in turn improves metabolic health via multiple interlocking pathways.

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Protein restriction and nutrient-sensing pathways

Another profoundly impactful biological effect of fasting that is also induced by protein restriction, is autophagy. Autophagy - literally ‘self eating’ - is the process by which our cells break down any unnecessary or damaged components, and recycle them into energy sources and functional building blocks. Autophagy is an anti-aging mechanism that is believed to account for a significant proportion of the therapeutic effects of fasting.

An enzyme with the catchy title mechanistic target of rapamycin (mTOR) is “a key modulator of ageing and age-related disease”. mTOR responds to nutrient sufficiency by blocking autophagy. Conversely, decreased availability of amino acids - the building blocks of protein - inhibits mTOR and consequently, facilitates autophagy. Let me ram this point home, in case you missed it: when you supply the body with an abundance of nutrients, including protein, the key process by which the body ‘cleans house’ - autophagy - is suppressed, and hence, cellular aging is accelerated.

Inhibition of mTOR by the drug rapamycin has been found to improve immune function, reduce cellular senescence markers and improve physical function in elderly people. Rapamycin, however, has a fairly high frequency of adverse effects including chronic mouth ulcers, bone marrow suppression, reduction of male fertility and increased serum total and LDL cholesterol. Restricting dietary protein - and in particular, the amino acid leucine, which is most concentrated in animal-sourced proteins - presents a far safer option for reducing mTOR activation and hence upregulating autophagy.

Aside from prompting FGF21 secretion and suppressing mTOR, protein restriction has been shown in animal research to decrease senescence in liver, kidney and fat cells; improve mitochondrial function; and prompt pro-longevity epigenetic modifications.

But don’t older people need more protein to prevent frailty?

That’s a very popular idea. Pretty much every self-styled nutrition ‘expert’ on YouTube, Instagram and Tiktok exhorts their hapless followers to “eat more protein” in order to get stronger and leaner. Older folk, and particularly older women, are urged to up their protein intake, to prevent the muscle and bone loss that leads to frailty and increased fracture risk. And yet, to describe the evidence that supports this advice as thin, is to overstate its strength. An overview of 33 meta-analyses and systematic reviews of randomised controlled trials conducted in older people (441 unique studies), found that

“There was no increase in muscle mass, strength or physical performance from protein supplementation in older people in general, nor in healthy older people.”

Effects of supplemental protein in older people: an overview of meta-analyses

In older adults with long-term conditions such as sarcopenia or frailty, the review found “medium-certainty evidence of at least small increases in muscle mass and strength in older people”; there was greater certainty of benefit when protein supplementation was combined with exercise. Patients hospitalised for hip fracture had fewer medical complications when supplemented with protein, although the review’s authors noted that hip fracture patients are routinely undernourished, so protein supplementation in this population may be more a matter of correcting frank malnutrition than of augmenting a normal or average protein intake.

A systematic review of 13 randomised controlled trials enrolling a total of 1057 participants aged 65 years and over who had been diagnosed with primary sarcopenia (age-related loss of muscle mass, strength and physical performance) or physical frailty, found that protein supplementation alone yielded only modest strength gains and limited benefits for physical performance. Significant improvements in muscle mass and grip strength were only seen in trials that combined protein supplementation with exercise - an important point which we’ll return to later. The quality of evidence was rated as “very low”, meaning the trials were methodologically weak and/or the data analysis was questionable.

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OK, but maybe by the time you get to older age, it’s too late to benefit from increased protein intake, so you should eat a higher protein diet earlier on in life to maximise your muscle mass? Actually, no: a systematic review and meta-analysis of randomised controlled trials investigating the effects of increased protein intake in healthy adults, found no significant increase in lean body mass, lower body strength, handgrip strength or physical function in participants who were fed a higher protein diet without an accompanying exercise program. Once again, benefits were only seen when increased protein intake was combined with resistance exercise training and even then, the effect of adding protein was marginal compared to the effect of the exercise. Participants randomised to eat more protein in conjunction with a resistance training program only gained 500-600 g more lean mass than participants who just undertook the resistance training program. And the difference in lower body strength gain and bench press strength between the normal protein and higher protein diet group, was slight, with low quality of evidence.

And a systematic review and meta-analysis of 49 randomised controlled trials of resistance exercise with or without increased protein intake, from 17 countries, with a total of 1863 participants, found that upping protein intake made very little difference to important outcomes of resistance exercise programs. Participants gained an average of 1.1 kg of fat-free mass from undertaking a resistance training program. Those who also increased their protein intake only gained an extra 300 g. Likewise, resistance training programs increased participants’ average 1 repetition maximum (1RM) strength (i.e. the maximum amount of weight that an individual can lift once) by 27 kg; those who were also eating extra protein only added 2.49 kg to their 1 RM strength. And while resistance training increased participants’ mid-femur cross-sectional area by an average of 52 mm² (indicating substantial thigh muscle growth), protein supplementation only added an extra 7.2 mm².

Let’s pause to underline this point: The leading modifiable cause of the loss of lean mass and strength that characterises sarcopenia and leads to frailty, is not protein deficiency, but physical inactivity. Hence, the most important element of programs to prevent and treat it is physical activity, and in particular, resistance training. Generally low-quality evidence suggests a small additive benefit of increased protein intake, but eating more protein without engaging in resistance exercise won’t help you retain or gain muscle mass or strength.

OK, eating more protein may not be that helpful, but it won’t hurt me... will it?

Actually, the results of research conducted in humans - not lab rats - including several cohort studies that have been running for decades - indicate that high protein diets increase the risk of multiple disease conditions. There’s some nuance here though: The source of that protein - which foods it comes from - determines whether it’s helpful or harmful to health, or simply neutral.

The authors of the review cite some of this research:

“However, accumulating evidence challenges the idea that higher protein intake is beneficial. Human association studies have found that high-protein diets are associated with an increased risk of diabetes, cancer, and mortality,^25,26 as well as an increased risk of death due to cardiovascular events.^27,28 An analysis of the National Health and Nutrition Examination Survey (NHANES) data found that higher protein consumption correlates with increased mortality and age-associated disease incidence, including diabetes.^25,26,29 A 2023 study in the UK reported that increased dietary protein intake was positively associated with sarcopenia in older twins, challenging the conventional idea that dietary protein prevents sarcopenia.^30,31,32,33”

The hallmarks of protein and amino acid restriction in aging and longevity

The studies cited in this passage include:

European Prospective Investigation into Cancer and Nutrition (EPIC)-NL study (reference # 25): 38,094 participants, ten years of follow-up.
Main findings: Participants with the highest intake of total protein had 2.15 times the risk of developing type 2 diabetes as those with the lowest intake. For animal protein, the risk was 2.18 times higher in the highest vs lowest consumers. There was no relationship between plant protein and diabetes risk.

Third National Health and Nutrition Examination Survey, 1988–1994 (NHANES 3) (reference # 26): 6381 respondents aged 50 plus, with 18 years of mortality follow-up via the National Death Index.
Main findings: In participants who did not have diabetes at the time they responded to the survey, those reporting a high protein intake had a 73-fold increase in risk of dying from diabetes during the follow-up period compared to those reporting low protein intake, while those reporting moderate protein intake had an almost 23-fold increased risk.
In respondents aged 50–65, those reporting high protein intake levels had a 74 per cent increase in their relative risk of all-cause mortality, and a greater than four-fold risk of dying of cancer compared to the low protein group. Moderate protein consumers had a 3-fold higher cancer mortality.

“However, when the percent calories from animal protein was controlled for, the association between total protein and all-cause and cancer mortality was eliminated or significantly reduced, respectively, suggesting animal protein mediates a significant portion of these relationships. When we controlled for the effect of plant-based protein, there was no change in the association between protein intake and mortality, indicating that high levels of animal proteins promote mortality and not that plant-based proteins have a protective effect.”

Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population

Low protein intake in respondents aged over 65 was still protective against diabetes mortality, but increased the risk of all-cause and cancer mortality compared to moderate and high protein intake. The authors speculated that “the dramatic switch from the protective to the detrimental effect of the low protein diet coincides with a time at which weight begins to decline” - that is, around 65 - and that increasing protein intake at this age may offset weight loss and accompanying frailty.

The Women’s Lifestyle and Health cohort study (reference # 27): 42,237 Swedish women aged 30–49 years old at baseline, followed up for 12 years.
Main findings: For each decile increase in protein intake, total mortality was increased by 2 per cent and cardiovascular mortality by 16 per cent.

The Kuopio Ischaemic Heart Disease Risk Factor Study (reference # 28): 2441 Finnish men aged 42 to 60 years at baseline, followed up for 22 years.
Main findings: Participants with the highest intake of animal protein had a 43 per cent higher risk of developing heart failure during the follow-up period, while plant protein intake was not associated with heart failure risk.

The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study (reference # 29): 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from eight European countries, with an average follow-up time of 12 years.
Main findings: Every 10 g of additional total protein intake was associated with a 6 per cent higher risk of developing type 2 diabetes, and every 10 g of additional animal protein intake with a 5 per cent higher risk. In obese women, the association was much stronger: a 19 per cent higher risk of developing type 2 diabetes for every 10 g of additional animal protein. Plant protein intake was not associated with the risk of type 2 diabetes.

Finally, the twin study referenced was a cross-sectional (i.e. single point in time) study of 3302 participants in the TwinsUK cohort, who were aged 60 or over. No significant association between protein intake and muscle strength was found, but high protein intake (more than 1.3 g of dietary protein per kg of body weight per day) was associated with 76 per cent higher odds of having low muscle mass, while low protein intake (less than 1 g/kg/day) appeared protective (48 per cent lower odds). For sarcopenia (defined in this study as accelerated loss of muscle mass and function), high protein intake was associated with double the odds.

The relationship between lower protein intake and better future health outcomes is reflected in intervention studies in humans who are already ill; again, the authors discuss several of these:

“In 2016, we reported that individuals consuming a low-protein diet for 43 days exhibited decreased body weight and fat mass and reduced fasting blood glucose despite increased caloric intake, mirroring our findings in rodents.³⁴ A recent study in lean men found that a 5-week PR [protein restriction] intervention improves insulin sensitivity and increases energy expenditure.³⁵ In the context of diabetes, short-term (27 days) PR was shown to reduce adiposity, improve insulin sensitivity, decrease circulating glucose and lipid levels, and reduce overall inflammation in patients with metabolic syndrome.³⁶ Additional studies have found that PR lowers blood levels of insulin and hemoglobin A1C and improves kidney disease outcomes in diabetic patients.³⁷ Conversely, a high-protein, low-carbohydrate diet was recently shown to be less effective than a moderate-protein diet in lowering blood glucose, improving glucose tolerance, and promoting prediabetes remission.^38”

The hallmarks of protein and amino acid restriction in aging and longevity

To sum up, observational studies suggest that higher dietary intake of total and animal protein promotes cardiometabolic disease whereas plant protein does not, while intervention studies show that cardiometabolic derangement manifesting as excess body fat, insulin resistance, elevated blood glucose and insulin, and inflammation, can be reversed by restricting protein consumption.

So, should everyone be eating less protein if they want a longer healthspan and lifespan? Not necessarily. Some people are consuming less protein than optimal, especially many frail elderly people with low appetites and limited budgets, and crash dieters - including people using appetite-suppressing GLP-1 agonist drugs like Wegovy and Ozempic. And there’s one other category of people who may either need a higher protein intake for optimal performance, or in whom the damaging effects of excess protein may be offset: physically active people.

The athlete exception

The authors of the review acknowledge that

“Those who are exercising may have higher protein needs or at least be able to consume higher levels of protein or specific amino acids without metabolic risk.”

The hallmarks of protein and amino acid restriction in aging and longevity

And, in an interview, lead author Dudley Lamming of the University of Wisconsin-Madison’s Department of Medicine and Comprehensive Diabetes Center stressed that

“It’s absolutely crystal clear that there are benefits of protein to muscle growth and exercise response of active individuals... But because most people are relatively sedentary, many people are likely consuming more protein than they actually need, which probably has negative health consequences.”

Protein Restriction Improves Metabolism and Longevity

And this is exactly what I tell my clients, when they ask me if they should be “eating more protein”:

Refer a friend

If you are engaging in significant endurance activity - for example, long-distance running or cycling, not jogging around the neighbourhood or doing a couple of aerobics classes per week - you need a higher intake of protein for muscle repair and (to a far lesser extent) to replace amino acids oxidised for energy during prolonged exercise.

And if you are doing meaningful strength training - a progressive overload program in which you are challenging your muscles beyond their current capacity by continually increasing the weight/resistance, frequency, or number of repetitions, not just doing push-ups and air squats every now and again - then you will see a small but measurable increase in your muscle mass and strength, if you increase your protein intake to around 1.2-1.6 g per kg of body mass per day, with younger people benefiting more from additional protein than older people, and those already undertaking strength training benefiting more than novices.

However, if you think that you’re going to transform your body composition simply by eating extra protein, you’re utterly deluded. In order to build muscle and decrease fat mass, you need to actually get off the couch and subject your body to the controlled form of stress known as exercise. And it’s important to know that performing resistance exercise in itself enhances muscle protein synthesis, regardless of protein intake. So your first step is to incorporate into your schedule at least two strength training sessions per week, in which you systematically work all the major muscle groups. Each week, your training volume should increase as you grow stronger, until you’re lifting a very respectable amount of weight for your age, sex and body size.

After you’ve been regularly performing resistance exercise for a couple of months, upping your protein intake will help you squeeze out some extra gains. Contrary to popular prejudices, plant-derived proteins are just as effective as animal-derived proteins for promoting muscle growth and muscle strength.

And on top of all the chronic disease risks mentioned previously, higher animal protein intake is associated with an increased risk of frailty (fatigue, low strength, reduced aerobic capacity, having five or more illnesses, and weight loss of five per cent or more), whereas higher intake of plant protein is protective against frailty. So if you’re augmenting your protein intake by bumping up your intake of plant foods such as tofu, tempeh, lentils, dried beans and seeds, you’ll get the best of both worlds: enhanced muscle mass and strength gains from resistance exercise, along with protection against cardiometabolic disease. That’s a pretty good deal, if you ask me.

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For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine.

To view the sources (links to articles, graphs, images and videos) that I referenced in this article, please visit the text version of this post:

As always, your feedback is greatly appreciated:

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For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine.

In some cases, the answer is simple: greed. Many ‘integrative’ doctors charge appointment fees that are far above Medicare or private insurance rebate rates, and if they’re subjecting patients to completely useless blood and/or saliva tests, supposedly to optimise hormone dosage, they’ll generate multiple repeat visits. Some even sell compounded hormone preparations to their patients. Ka-ching, ka-ching.

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What about the well-meaning practitioners who aren’t intentionally fleecing their patients? Most of these cases can be explained by ignorance. Unaware of the vast sums of money spent by the pharmaceutical company Wyeth (acquired by Pfizer in 2009) to smear the Women’s Health Initiative trial that led to a precipitous decline in prescriptions for hormone replacement therapy, these doctors have apparently been suckered by claims spawned by the Wyeth-funded campaign.

Prominent among these claims is the critical period or timing hypothesis. That is, critics of the Women’s Health Initiative study argue that the negative results that led to its premature termination - namely increased risk of coronary heart disease, stroke, pulmonary embolism and breast cancer - and the subsequent finding that women who took combined HRT had double the risk of developing probable dementia, apply only to women who started hormone therapy well after they had gone through menopause. Conversely, they assert, women who commence taking hormones within a few years of menopause are not subject to these risks... and in fact, observational studies (i.e., non-randomised trials) suggest that they will benefit, with a reduced risk of Alzheimer’s disease and cardiovascular disease, along with decreased all-cause mortality.

Another claim of the new crop of menopausal hormone therapy spruikers, is that the negative effects of hormone therapy that were found in the Women’s Health Initiative study, were due to the types of hormones used - namely, conjugated equine (horse-derived) estrogen and progestin (synthetic progesterone), both taken orally. According to this argument, transdermal estradiol - that is, an estrogen preparation that has the same chemical formula as the type of estrogen made by women’s ovaries1, but is delivered via a patch, cream, gel or lotion - and bioidentical progesterone, which are used in present-day menopausal hormone therapy, do not have the drawbacks of earlier HRT drug regimens.

In fact, these enthusiasts claim that by maintaining estrogen and progesterone at levels comparable to those in premenopausal women, bioidentical hormone therapy may protect women from the increased risk of diseases whose incidence climbs dramatically after menopause, especially cardiovascular disease, stroke, dementia and cancer. And many also tout hormone therapy for mood disorders that a lot of women suffer as they go through the menopause transition.

Sounds pretty appealing, doesn’t it? Who wouldn’t want to prevent those nasty diseases, if they could? And there’s some biological plausibility to these claims. After all, every cell in the body - including the brain - has receptors for estrogen, and the hormone does appear to play a major role in facilitating the lower rate of cardiovascular disease that premenopausal women enjoy, compared to men of the same age - protection that evaporates after women go through menopause.

But if there’s one thing we should have learned from the history of drug trials, it’s that plausible mechanisms don’t always translate into beneficial clinical outcomes. That is to say, just because something should work, based on its mechanism of action, doesn’t mean it will work, in the sense of delivering a net benefit to health. So let’s examine the evidence for these two claims.

Firstly, does menopausal hormone therapy, whether oral or transdermal, protect women against dementia when they start taking it within the “critical window” - that is, ten years or less after going through natural menopause?

Dementia, Alzheimer’s disease and cognitive decline

As Barbara Mintzes and Adriane Fugh-Berman point out in a commentary published in the BMJ Drugs and Therapeutics Bulletin in December 2024, the Women’s Health Initiative study that the MHT enthusiasts love to hate on, did in fact enrol almost 9000 women aged 50-59. 1326 of these women were included in the Women’s Health Initiative Study of Younger Women (whimsically abbreviated ‘WHIMSY’). After an average follow-up period of 14 years, WHIMSY found no overall difference in cognition between women who had been randomised to receive hormone therapy (oral conjugated equine estrogen, with or without medroxyprogesterone acetate) and placebo recipients. However, women who had taken estrogen-only hormone therapy performed slightly worse in tests of verbal fluency.

Were the disappointing results seen in WHIMSY the consequence of using the older formulation of menopausal hormone therapy, namely conjugated equine estrogen, taken orally? To answer this question, the Kronos Early Estrogen Prevention Study (KEEPS) randomised women within three years of natural menopause to receive either oral conjugated equine estrogens or transdermal 17β-estradiol, or placebo. Both estrogen therapy groups also received oral micronised progesterone (200  mg/d) for the first 12 days each month, in place of the synthetic progestin used in the Women’s Health Initiative. After four years of follow-up there were no effects of either form of estrogen therapy on cognition, for better or for worse.

A systematic review of placebo-controlled randomised trials on menopausal hormone therapy with either oral or transdermal estrogen plus progesterone or a progestin, in spontaneously menopausal women under the age of 60 identified nine such trials which evaluated cognitive outcomes in a total of 2452 women. No benefits of either type of estrogen therapy on cognition were identified.

And an as-yet-unpublished systematic review and meta-analysis identified ten studies enrolling a total of 213,678 participants who commenced taking hormone therapy (either oral or transdermal estrogen), with or without synthetic or bioidentical progesterone, within five years of menopause. Of the ten studies, three were randomised controlled trials, three were nationwide nested case-control studies and the remaining four were prospectively gathered cohorts from population databases. Outcomes assessed included dementia diagnoses (including Alzheimer’s disease), cognitive decline and mild cognitive impairment.

Meta-analysis found no increased risk of all-cause dementia in women who began taking menopausal hormone therapy between the ages of 45 and 60, but a 14 per cent higher risk of developing Alzheimer’s disease in women with a uterus and 12 per cent higher risk in those without. Longer duration of use conferred higher risk. No protection against cognitive decline or mild cognitive impairment was found.

In summary, menopausal hormone therapy with either oral or transdermal estrogen, has not been found to improve cognitive outcomes, reduce cognitive decline, or prevent dementia, and may in fact increase the risk of Alzheimer’s disease, especially with prolonged use.

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Cardiovascular disease

The systematic review of nine randomised controlled trials of menopausal hormone therapy referred to in the previous section, also identified three trials which evaluated outcomes related to cardiovascular disease, in women who commenced therapy within ten years of naturally-occurring menopause. Of these, the Women’s Health Initiative identified no cardiovascular benefit of taking oral conjugated equine estrogen plus medroxyprogesterone acetate in women aged 50-59, and a protective effect of conjugated equine estrogen alone on some cardiovascular outcomes (coronary heart disease, coronary revascularisation, and a composite measure of cardiovascular death plus coronary revascularisation), but an increased risk of stroke.

The other two trials found no benefit of either oral or transdermal estrogen therapy plus micronised progesterone or medroxyprogesterone acetate (in women with a uterus), on cardiovascular disease.

In summary, women with a uterus derive no benefit of menopausal hormone therapy when it comes to preventing cardiovascular disease; the observed benefit for women without a uterus may be attributable to offsetting of the negative cardiovascular effects of oophorectomy (surgical removal of the ovaries).

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Cancer

In women aged 50-59 at enrolment in the Women’s Health Initiative, there was a 36 per cent higher risk of invasive breast cancer at 20-year follow-up in those randomised to conjugated equine estrogen plus medroxyprogesterone acetate. Women taking estrogen alone did not have an increased risk, but the authors of the study speculated that this might have been because those with a longer time between undergoing oophorectomy and commencing estrogen therapy, were protected from invasive breast cancer.

There was no difference in the risk of endometrial or colon cancers in women taking hormones vs placebo.

In summary, women who commenced taking conjugated equine estrogen plus medroxyprogesterone acetate under the age of 60 had an increased risk of invasive breast cancer. No randomised controlled trials have examined the risk of cancer in women using transdermal estrogen.

Depression and low mood

Nine randomised controlled trials enrolling a total of 1280 women between the ages of 40 and 60 have evaluated the effects of oral conjugated equine estrogen, oral 17β-estradiol, or transdermal 17β-estradiol on depression and other mood states.

Of these, six found that hormone therapy improved some aspect of mood, while three found no effect on any mood endpoint. Of the five studies that specifically examined depression, two found that hormone therapy improved depression scores, while three reported no difference in depression scores between women assigned to hormone therapy vs those who received placebo.

Transdermal estrogen did not outperform either oral conjugated equine estrogen or oral 17β-estradiol, and three out of the four studies of transdermal 17β-estradiol therapy found no difference between hormone and placebo groups.

Studies that differentiated between mood symptoms related or unrelated to sleep disruption from vasomotor symptoms (hot flushes/flashes and night sweats), found that only women whose sleep quality was improved by menopausal hormone therapy experienced better mood.

In summary, evidence from randomised controlled trials does not support the claim that menopausal hormone therapy improves mood or prevents depression, except to the extent that it relieves vasomotor symptoms that interfere with sleep and quality of life.

The bottom line

Menopausal hormone therapy is approved for only two indications: relief of vasomotor symptoms (hot flushes/flashes and night sweats), and mitigation of loss of bone mineral density. For women with medical contraindications to hormone therapy (e.g. personal or family history of breast cancer, or thromboembolic disease), or those who just don’t want take drugs to manage this perfectly natural and normal life-stage, there are highly effective Lifestyle Medicine approaches to relieving vasomotor symptoms, improving body composition and bone density, reducing the risk of cardiovascular disease and relieving depression and improving psychological well-being, which I discussed at length in Drug-free treatments for perimenopausal symptoms (Part 3 of The Menopause Files).

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Ted touched on Lamarckian inheritance in our previous conversation, Life, the Universe and Everything:

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In this conversation, we focused in on the details of how Lamarkian inheritance shows up in living creatures, and the mechanisms that researchers have discovered by which these inheritance patterns can actually occur.

What we discussed:

• The development of evolutionary theory in the 19th century. Jean-Baptiste Lamarck’s theories of inheritance of acquired characteristics, preceded Charles Darwin’s development of the theory of evolution by natural selection, driven by random mutation of genes. Darwin actually endorsed Lamarck’s theories, but his champions subsequently insisted that Lamarck was wrong, and that traits acquired after an individual’s birth could not be passed on to its offspring.

• Evidence for Lamarckian inheritance. Ted asserts that instinctive behaviours are evidence of Lamarckian inheritance. He also describes the immune system as “the tip of the spear of such inheritance of acquired changes. Furthermore, many animal experiments demonstrate inheritance of acquired behaviours and characteristics.

• Overlap between epigenetic programming and Lamarckian inheritance. According to Ted, epigenetic programming - that is, alteration of structure or function of offspring because of environmental circumstances experienced by the father or mother - is a form of ‘soft’ Lamarckian inheritance, while if similarly-impacted offspring inbreed or interbreed, these alterations will be locked in as ‘hard’ Lamarckian inheritance - that is, permanent alterations in the genetic code.

• Mechanisms for Lamarckian inheritance. Multiple mechanisms by which Lamarckian inheritance could occur have been discovered and characterised, including reverse transcriptase which ‘writes’ environmentally-driven changes in RNA into DNA.

• Incorporating Lamarckian inheritance mechanisms solves problems with ‘mainstream’ evolutionary theory. Not the least of these problems is the fact that random mutation occurs too slowly to explain the timeline of species development… including our own.

• What it’s like to be a heretic in the scientific field. When Ted commenced his scientific career in the 1970s, even exploring Lamarckian ideas marked one out as a heretic! Voluminous evidence for such ideas has accumulated since then, but mainstream evolutionary biology still refuses to acknowledge it.

• Thomas Kuhn’s notion of paradigm shifts… and what drives them (eventually), which is an accumulation of data that simply does not fit the dominant paradigm.

• The need for funding of basic research to test hypotheses of Lamarckian inheritance. And some of the obstacles to such funding!

  Thanks for reading Empowered! This post is public so feel free to share it.

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Further reading:

‘Epigenetic–Genetic Coupling and Understanding the Molecular and Cellular Basis of Lamarckian Inheritance’ by Robyn Lindley, Reginald Gorczynski and Edward Steele.

‘The Evidence For Lamarck’ by Edward Steele.

The Case of the Midwife Toad by Arthur Koestler - free version on Archive.org.

Lamarck’s Signature: How Retrogenes Are Changing Darwin’s Natural Selection Paradigm by Edward J. Steele, Robyn A. Lindley and Robert V. Blanden - free version on Archive.org, or support the authors and buy a copy.

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On the other hand, many proponents of time-restricted eating2 suggest limiting one’s food consumption to an eight-hour ‘eating window’, typically between 12 pm and 8 pm. And there’s even a small but vocal faction who advocate ‘OMAD’ - One Meal A Day. Both of these protocols almost inevitably result in the majority of calories being eaten at night. So who’s got the right idea - the breakfast maximalists, or the breakfast skippers?

According to a meticulous study on eating timing and metabolic efficiency, carried out by German researchers, eating the bulk of one’s calories earlier in the day is definitely the best plan, if you want to maximise insulin sensitivity and decrease your risk of developing diabetes. The fly in the ointment is that meal time preference has strong genetic influences, making it rather difficult to shift. So is it worth making that effort, if you’re a night owl who tends to eat most of your calories later in the day? Let’s dig into the study, to find out.

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Chrononutrition: The new frontier of nutrition science

Chronobiology - the study of the influence of the circadian rhythm3 on biological function - is a burgeoning field of research. Among its major sub-fields is chrononutrition - the relationship between the timing of our meals, and what our bodies do with the food we eat:

“Our body reacts differently to the same food consumed at different times of the day, showing diurnal variation in glucose tolerance, postprandial [after-meal] hormone secretion, thermogenesis [after-meal ‘calorie burn’], metabolite levels, and other metabolic processes.”

Later eating timing in relation to an individual internal clock is associated with lower insulin sensitivity and affected by genetic factors

In other words, the very same meal has vastly different metabolic effects, depending on whether you eat it as breakfast or as dinner (‘supper’ or ‘tea’, for our English friends). Regardless of its size or composition, that meal, when eaten in the morning, will require less insulin secretion, and produce a smaller ‘bump’ in blood glucose level and a greater after-meal calorie burn, resulting in less of it ending up in fat stores than if you were to eat it at night.

Another field of study within chronobiology is chronotype - the tendency of individuals to be ‘morning larks’ (early chronotype) who naturally rise early and go to bed early; ‘night owls’ (late chronotype) who gravitate toward sleeping in and going to bed late, and intermediate chronotypes who are somewhere between these extremes. Chronotype is strongly heritable, meaning that our genes exert a powerful influence on our preference to either rise early and fade with the sunset, or to come alive at night.

The confluence between chrononutrition and chronotype makes twins an interesting group to study. Why? Because there are two types of twins: monozygotic twins - commonly called ‘identical twins’ - who result from a single sperm fertilising a single egg, which subsequently splits in two; and dizygotic twins - also known as fraternal or nonidentical twins - who develop from two separate eggs fertilised by two separate sperm cells. Monozygotic twins have exactly the same genes, whereas dizygotic twins are only as genetically similar to each other as are any two siblings, sharing roughly 50 per cent of their DNA4. So if you want to tease out the effects of genes vs environment (including upbringing) on various behaviours and health outcomes, a combination of monozygotic and dizygotic twins, with each twin pair having been raised together, is just what the scientist ordered.

The German researchers recruited 46 twin pairs without diabetes, of which 32 were monozygotic and 12 were dizygotic. All participants took an oral glucose tolerance test to assess their insulin sensitivity; kept detailed written food records for five days, specifying what, how much, and when they ate; and also noted when they woke up, and when they felt ready to fall asleep.

From these data, the researchers first sorted participants into early, intermediate and late chronotypes. Then, the clock times at which participants had recorded their food intake were adjusted for chronotype, to derive circadian times of their onset of first eating occasion, cessation of latest eating occasion, and caloric midpoint (the time at which they had consumed half of their daily calorie intake).

This adjustment from clock times of meals to circadian times was made to account for the fact that one’s individual biological circadian rhythm plays a major role in chrononutrition. For example, if a morning lark who’s up’n’at’em at 5 am and fast asleep by 9 pm, were to eat breakfast at 9 am and dinner at 7 pm, these meals would be late according to their personal circadian phase. But these same meal times would be early for a night owl who rolls out of bed at 8.59 am and goes to sleep at 1 am.

Considered as a whole, participants consumed on average 24 per cent of their daily calories in the first meal, and 34 per cent in the last meal, with the caloric midpoint of intake at around 3:50 pm (clock time).

But later chronotypes consumed more of their calories in their last meal, and hence had a later circadian time of the caloric midpoint - that is, their calorie intake was shifted into the latter part of their day, even after accounting for the fact that they got up and went to bed later than the early chronotypes.

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The metabolic consequences of late eating

Having a later circadian time of caloric midpoint was associated with poorer insulin sensitivity and greater insulin resistance, meaning that participants who ate the bulk of their calories later in their circadian day had to secrete more insulin to deal with the post-meal rise in blood glucose level, and their blood glucose stayed elevated for longer, compared to those who stacked their caloric intake into the earlier part of their circadian day. The late eaters also had a higher fasting insulin level, body mass index (BMI), waist circumference, and waist-to-hip ratio - all indicators of poorer metabolic health. Disposition index, a measure of the relationship between insulin secretion capacity and insulin sensitivity and hence a predictor of conversion from insulin resistance to type 2 diabetes, was also associated with circadian time of caloric midpoint, suggesting that consuming most of one’s calories early in the day may be protective against diabetes.

Conversely, those who consumed a higher percentage of their daily calories in the first half of their circadian day had a lower fasting blood glucose level and better glucose tolerance.

The short-and-sweet summary of these findings is that if you want to reduce your risk of developing type 2 diabetes, you should eat more of your calories at breakfast and lunch and less at dinner, regardless of what time you eat your meals.

Meal time preference: Nature, nurture or current environment?

Turning to the genetic influence on chronotype and meal timing, the researchers found that monozygotic twins were more likely than dizygotic twins to share a chronotype, which confirmed previous research showing that chronotype is highly heritable - that is, more than 50 per cent of the variance between individuals in personal circadian rhythm, is attributable to genetic factors. Likewise, monozygotic twins were more likely to have similar meal timing patterns. The only exception was duration of eating window, which showed a stronger correlation in fraternal than identical twins.

The circadian time of the last meal of the day, however, was less influenced by genetic factors than the first meal, which led the researchers to suggest that trying to eat breakfast earlier than one is naturally inclined to do, would be harder than shifting dinner to an earlier time. (As a practical matter, however, many people’s evening meal time is dictated by external factors over which they have little to no control, such as what time they get home from work, and their children’s extracurricular activities.)

One other finding of note was that the length of the eating window showed no associations with BMI, waist circumference or glucose tolerance, confirming other studies which did not find any benefits of time-restricted eating for weight management or metabolic health.

The bottom line

Chrononutrition research is providing ever more evidence that while what we eat is of paramount importance to health, when we eat it is an important factor too. Data from various studies, including the German one discussed above, converges on a single message: Stacking your calories earlier in the day is an important strategy for avoiding weight gain and maintaining insulin sensitivity, which reduces your risk of developing cardiometabolic diseases including type 2 diabetes.

If you’re a lifelong breakfast-skipper who just can’t summon up an appetite in the morning, don’t despair! The first step to take is to shift the timing of your final meal of the day, so that you finish eating earlier - at least two hours before going to bed, and preferably three hours. Once you polish off dinner, floss and brush your teeth so that you’re not inclined to snack throughout the evening. If you practise this habit consistently, you’ll find yourself getting hungry earlier the following day, which will facilitate a gradual transition toward eating more of your calories in your circadian morning, regardless of your chronotype.

And for those who tried to implement time-restricted eating but had trouble delaying their daily eating start-time, the good news is that you can relax! There’s no magic in maintaining a shorter eating window.... and in fact, late time-restricted eating - that is, a shorter eating window in which calorie consumption is pushed into the second half of the day - appears to be counterproductive.

Finally, comparison of fraternal vs identical twins sheds light on the power of genetic influences to shape our chronotype and meal timing preferences. But in this case (as in most conditions and behaviours with high heritability), genes are not destiny. It is possible to shift your meal timing and distribution of calories to a healthier pattern, if you have the motivation to do it. And avoiding type 2 diabetes - a truly horrible condition that can lop as many as 14 years off your life expectancy - ought to be a good motivation to make these changes!

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As always, your feedback is greatly appreciated:

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• Hormonal contraception and women’s mental health

• More evidence that taking the Pill in your teens is linked to depression

• This is your brain on the Pill

• More proof that the oral contraceptive pill causes depression

• New study finds all forms of hormonal contraception raise breast cancer risk

• How the Pill and HRT affect your gut… and your risk of autoimmune and inflammatory disease

And now, new research published in JAMA Network Open has added another risk to Pill users, on top of depression, anxiety, breast cancer, autoimmune disease, a shrunken hypothalamus and blunted stress reactivity: binge eating.

Binge eating is defined as “consumption of a large amount of food, in a short period of time, with a loss of control over eating”.

Many women report some changes in appetite and in the intensity and target of food cravings, associated with the phases of their menstrual cycle. Unfortunately for those who would like to justify devouring a family-sized block of Cadbury’s Dairy Milk in one sitting by attributing it to a biological requirement for chocolate (trust me, more than a handful of clients have tried this one out on me), it turns out that premenstrual chocolate cravings are in fact a purely cultural phenomenon. Only four per cent of Spanish women vs forty per cent of American women report premenstrual chocolate cravings, with immigrants to the US reporting more intense chocolate cravings, the more they become acculturated.

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However, there does appear to be a biological basis for overeating, binge eating and emotional eating1 in the second half of the menstrual cycle, between ovulation and the onset of menstruation. The steroid hormones produced by women’s ovaries regulate reward systems in the brain, that use dopamine and opioids to reinforce consumption of high-calorie foods - especially those rich in fat and/or sugar. These reward pathways always fire off when we eat highly-palatable foods like chocolate, ice cream, cheese, processed meats and pastries, but they show increased activation in the post-ovulatory phase of women’s menstrual cycles.

The combination of higher estradiol2 and low progesterone levels in the preovulatory phase of the menstrual cycle tends to reduce food intake, while the post-ovulatory hormonal milieu of high estradiol and high progesterone is associated with increased food intake in both humans and non-human animals - especially of hyperpalatable food. And episodes of both binge eating and emotional eating occur more often in the postovulatory than the preovulatory phase.

OK, so women’s own ovarian-derived hormones can influence their propensity to overeat and binge eat. But what about the synthetic versions of estradiol and progesterone that more than 100 million women around the world take every day, in the form of oral contraceptives? That is, does being on the Pill cause women to binge eat or overeat for emotional reasons, more often than they otherwise would?

To find out, researchers recruited 422 women from the Michigan State University Twin Registry, who were already taking combined oral contraceptives (i.e. formulations that contained both a synthetic estrogen (most commonly, ethinyl estradiol) and progesterone (progestin). Only women using monophasic oral contraceptives (that is, those that provide a constant dose of synthetic estrogen and progestin across active pills) that contain 21 active pills and seven inactive or placebo pills per packet, were included, in order to narrow down the specific impact of a high-estrogen, high-progesterone hormonal milieu vs a low-estrogen, low-progesterone milieu, on the propensity to binge eat. Monophasics are also the most commonly-prescribed oral contraceptives, making the findings of this research very broadly applicable to Pill users.

For 49 consecutive days - incorporating two active-to-inactive pill transitions - participants filled in nightly online questionnaires on their eating behaviour, degree of weight preoccupation (mental fixation on dieting, weight, or body shape) and experience of negative affect (low mood and distressing emotions such as sadness, disgust, lethargy, fear, and distress) during the preceding day.

There was a marked increase in the frequency of emotional eating on the 21 days when participants were taking the active hormone pills, compared to when they were in the seven-day inactive pill phase. 51 of the participants were identified as experiencing clinically defined binge-eating disorder as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), and these participants also had substantially more frequent episodes of emotional eating whilst taking active hormone pills. This association between emotional eating and active hormone pill-taking was not accounted for by changes in negative affect or weight preoccupation, indicating that it was driven by the specific hormonal milieu of high (synthetic) estrogen and progesterone.

Interestingly, emotional eating episodes were less frequent during the second oral contraceptive pill cycle than the first:

The researchers speculated that self-monitoring - the act of paying attention to one’s eating behaviour, and being accountable for it through daily reporting - may have decreased the frequency of emotional eating episodes in the second Pill cycle, as this phenomenon has been reported in previous research.

Notably, not all women experienced increased frequency of emotional eating while on active hormone pills. Individual differences in genetic factors such as hormone metabolism or receptor activity; in epigenetic factors such as prenatal stress imprinting; or in early life experiences - or some combination of these factors - may conspire to make some women more susceptible to Pill-induced emotional eating and binge eating.

So if you’re struggling with binge eating, emotional eating or overeating, or a woman you love is battling with these disordered eating behaviours, the oral contraceptive pill might be part of the problem. This issue should be raised with the prescribing doctor, and you may want to print out the JAMA Network Open article and take it to the appointment.

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The study, published in JAMA Otolaryngology - Head & Neck Surgery, analysed electronic health records from the TriNetX Global Collaborative Network. TriNetX is a large database of electronic health records from “more than 13,000 clinical sites across 20+ countries worldwide”.

Researchers first pulled deidentified medical records of 438,474 patients with type 2 diabetes who had received at least two prescriptions for a GLP-1 drug. They then trawled the database to find 438,474 type 2 diabetic patients who were taking at least one other type of diabetes medication, but had not used GLP-1s. This second group was matched to the GLP-1-using cohort in terms of demographic characteristics, comorbidities, socioeconomic risk factors, nicotine dependence, and prior surgical procedures. Patients in both groups had no documented history of taste or smell disturbances as of December 2017, the date chosen as the study’s baseline. Then, the researchers compared the rate of new onset of smell and taste disturbances in the GLP-1 users and non-users, over the following two years.

(As an aside, this is one example of an appropriate and worthwhile use of artificial intelligence. A well-constructed algorithm can rapidly trawl through mountains of data that would take a whole team of humans several months, or even years, to process, enabling detection of drug safety signals that might otherwise not be picked up for decades. Whether these safety signals are acknowledged and acted upon by regulatory bodies and prescribing physicians, is another matter entirely, as we learned during the manufactured COVID crisis.)

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You might be wondering why the researchers focused on diabetic patients. Amid all the hoopla around GLP-1 receptor agonists as weight loss drugs, it’s easy to forget that they began life as an adjunctive treatment for type 2 diabetics who do not achieve adequate blood glucose control on metformin - the first-line medical treatment for the condition - or who cannot tolerate it. The problem is, GLP-1 receptor agonists may be giving diabetics better numbers on their blood tests, while failing to prevent diabetic complications such as nerve damage... or perhaps even accelerating the development of complications, at least in some patients.

So what is the connection between taste and smell disturbances, and diabetic complications? Diabetes is characterised by persistently high blood glucose levels, which cause damage to both nerves - known as diabetic neuropathy - and to small blood vessels - microvascular complications. Diabetics are known to be at higher risk of smell and taste disturbances, and it is believed that these sensory disorders are caused by diabetic neuropathy and microvascular damage. Moreover, taste and smell disturbances aren’t just inconveniences, or minor threats to one’s quality of life. They are indicators of neurodegenerative disease and predictors of shortened lifespan in both the general population, and specifically in diabetics. Smell or taste disorders in diabetics are a marker of worsening health and higher risk of more severe - and potentially life-shortening - complications.

So what exactly did the researchers find? Overall, the risk of smell and taste disorders was increased by 48 per cent in diabetics who had used a GLP-1 receptor agonist. When broken down into separate categories, risks were as follows:

• Olfactory disorders (disorders of the sense of smell): 81 per cent higher

  • Anosmia (complete loss of the sense of smell): 78 per cent higher

  • Parosmia (distorted sense of smell): 118 per cent higher, or more than double the risk

• Gustatory disorders (disorders of the sense of taste): 52 per cent higher.

It’s important to point out that while GLP-1 users had a substantially increased relative risk of taste and smell disturbances, the absolute risk increase was relatively small - just 0.15 per cent. (For a concise explanation of relative vs absolute risk, see my previous article Fear-based medicine and the concept of risk.) In more easily relatable terms, that’s a number needed to harm (NNH) of 670 - that is, 670 type 2 diabetic patients would have to use at least two prescriptions of a GLP-1 receptor agonist, for one of them to develop a taste or smell disturbance.

However, this may be an underestimate of the magnitude of the effect, for two reasons:

1. Patients may not necessarily report disturbances of taste and smell to their doctor, perhaps because they don’t think it’s serious enough to mention, or they attribute it to ‘getting older’, or they assume it’s pointless to discuss because nothing could be done about it anyway.

2. Doctors may not use the correct International Classification of Diseases (ICD) code for the smell or taste disorder on the patient’s electronic medical record. The researchers used these ICD codes to identify patients who had developed taste and smell disturbances during the two year follow-up period.

But even if no more than one in every 670 GLP-1 drug users is afflicted by a taste or smell disturbance, it’s still an adverse effect that should be taken seriously.

Losing one’s sense of smell and/or taste, or having a distorted sense of smell or taste, impacts greatly on quality of life. I saw several clients who lost their sense of smell after getting COVID-19. All of them reported that not being able to smell food, or household odours, or the scents of nature, or their loved ones’ distinctive aromas, was profoundly distressing and disorientating. And altered or absent taste and smell perception can make it extremely difficult for a diabetic to follow a healthy diet, which is, of course, the most impactful step they can take to get their diabetes under control.

Perhaps most importantly, as mentioned previously, taste and smell disorders are an indicator of damage to the nerves involved in processing this sensory information, and hence are potentially early predictors of diabetic neuropathy. Let’s not forget that patients with diabetes take GLP-1 receptor agonists because their doctors tell them that by helping them achieve better blood glucose control, the drugs will stave off diabetic complications. But if taste and smell disorders are occurring at a higher rate in GLP-1 users than in patients taking other diabetic medicines, these drugs may be increasing the risk of diabetes-related neurological problems.

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The bottom line

I’ve written before about the misnomer of drug ‘side effects’. The desirable effects of a drug are described as its actions, while the undesirable ones are dubbed side effects or adverse effects. But in reality, all of the drug’s actions are effects, and more to the point, they’re all effects of interference with human physiology. If you’re sick, you can’t drug yourself back to good health, because health comes from healthful living. This is an immutable law of nature. Drugging people who became overweight and/or diabetic because they weren’t living healthfully, rather than addressing the causes of their condition is, in my opinion, completely insane.

As I wrote in The dark side of weight loss: Are GLP-1 agonists putting patients at risk for blindness, depression and suicidal thinking?, no less than 26 so-called ‘anti-obesity’ medications have been pulled from the market since 1964, because of safety issues ranging from toxicity to the heart and liver, to drug abuse and dependence, to psychiatric issues, to stroke and cancer... and the ultimate safety issue, namely death. GLP-1 receptor agonists may eventually face the same fate, but given the record profits they’re generating for the pharmaceutical industry, I’d say it’s odds-on that they will only be withdrawn after they’ve injured or killed millions of people.

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In the mean time, use of GLP-1 agonists has exploded. Between 2020 and 2025, total Australian sales increased almost tenfold. Semaglutide (Ozempic, Wegovy) accounts for the lion’s share of prescriptions, while tirzepatide (Mounjaro) use is surging:

Roughly half a million Australians - almost two per cent of the population - are currently using GLP-1 agonists, and supply-demand modelling performed by the multinational investment bank Morgan Stanley in 2024 predicted that up to 40 per cent of Australians could be on the GLP-1 train by 2030.

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GLP-1 agonists reduce spontaneous physical activity

Bearing in mind this burgeoning use, research presented at the 2026 annual conference of the Endocrine Society is quite alarming. In a poster presentation titled ‘Losing Pounds, Not Gaining Steps: The Paradox of GLP-1 Receptor Agonist Therapy’, researchers analysed data from 753 participants in the All Of Us Research Program, who had Fitbit activity data from both before and after they began using GLP-1 agonists to lose weight.

Contradicting the widely-held assumption that people will exercise more after losing weight, because a lighter body is easier and more enjoyable to move around, participants took an average of 560 fewer steps per day after initiating GLP-1 drugs (dropping from an average of 5047 to 4487 steps), and performed 5.7 fewer minutes of moderate-to-vigorous physical activity per day (from an average of 27.9 minutes per day down to 22.2 minutes/day). Step count is a decent proxy for spontaneous movement, while moderate-to-vigorous physical activity reflects intentional exercise.

Male participants experienced greater declines in both daily steps and moderate-to-vigorous physical activity than females. Participants suffering from musculoskeletal pain also decreased their daily step count significantly more than those not in pain. This is quite a counterintuitive finding. We would expect weight loss to ease painful joints and sore muscles, thus facilitating higher levels of activity. And considering that almost 82 per cent of participants reported suffering from musculoskeletal pain, this finding is also highly concerning.

The authors concluded that

“In this real-world cohort, initiation of GLP-1 RA [receptor agonist] therapy in obese patients led to a significant decrease in daily steps and MVPA [moderate-to-vigorous physical activity], with males and those with MSK [musculoskeletal] pain experiencing the greatest declines. These reductions in activity were not influenced by age, morbid obesity, stroke, or heart failure status. These findings suggest that weight loss alone may not promote increased physical activity, highlighting the need for future studies to explore targeted interventions that encourage physical activity alongside pharmacologic therapy.”

Losing Pounds, Not Gaining Steps: The Paradox of GLP-1 Receptor Agonist Therapy

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Why do GLP-1 agonist users move less?

The researchers were simply analysing movement data recorded by Fitbits, so they were not able to ascertain the reasons for participants’ decline in physical activity. A few possibilities immediately spring to my mind though:

1. Moral licensing. Also known as self-licensing and the licensing effect, this is a fascinating and well-documented phenomenon by which people give themselves permission to do something bad, after they’ve done something good. Think of the dieter who ‘treats herself’ to an indulgent dessert after a week of healthy eating - that’s moral licensing. So people may perceive that since they’re already doing something good for their weight by taking the drug, they can feel free to do something bad for their weight by being more sedentary.

2. Sarcopenia. GLP-1 agonists cause sharp reductions in muscle mass - far more so than regular dieting-induced weight loss. In fact, muscle loss can account for up to 40 per cent of weight lost on these drugs. With less muscle, physical activity feels considerably harder and less rewarding. The accompanying frailty can also reduce people’s confidence in undertaking exercise, due to fear of falling or suffering an injury.

3. Depression and reduced dopamine signalling. I previously discussed the evidence that GLP-1 agonists may induce depression and suicidal thoughts, or just make users feel ‘blah’, by reducing dopamine signalling. Although dopamine has long been thought of as a ‘pleasure chemical’, it is more accurately characterised as playing a key role in reward. The brain’s reward system utilises dopamine to evoke feelings of enjoyment and reinforcement, which then motivate us to continue or repeat the behaviour. Dopamine is also crucially involved in the initiation and regulation of movement. So it’s easy to see how GLP-1 agonist-induced downregulation of dopamine signalling could lead people to become less physically active.

Whatever the cause (or causes) may be of the decreased physical activity observed in people using GLP-1 agonists, the implications are disturbing. The authors of the new report point out that “long-term weight control is more effective when combined with regular exercise”... but if GLP-1 drugs lead to reduced physical activity, weight regain is far more likely. And we already know that roughly 10 per cent of people quit taking GLP-1 agonists because they can’t tolerate the side-effects, and they start regaining weight immediately.

Furthermore, weight loss plateaus after people have been on these drugs for a bit over a year, even if they continue using them. So at this stage GLP-1 agonist users are in a truly invidious position: The drug is no longer helping them to lose weight, but if they stop taking it they’ll gain back the weight they lost, which will now be much harder to shift because they’ve lost muscle mass and hence dialled down their metabolic rate.

In a nutshell, if this preliminary research is confirmed in larger studies, what we’re looking at is the prospect that tens of millions of people may have significantly reduced muscle mass as a direct consequence of using GLP-1 agonists, and that they will find it extremely difficult to do the volume of exercise required to halt or reverse this loss of muscle tissue, setting them up for not only weight regain but frailty and increased risk of bone fractures.

The exercise-mood connection

Furthermore, there’s a bidirectional relationship between physical activity and what researchers call affective well-being, which incorporates experiencing positive emotions, feeling energised, and feeling well and content. Drawing on studies which collected both movement data from accelerometers (like Fitbit), and self-ratings of affective well-being on smartphone-based electronic diaries, researchers analysed 67 datasets from 14 countries worldwide, incorporating data from 8223 participants.

They found that when individuals are more physically active than their own average, they report higher affective well-being at their next self-assessment. And on average, more active participants exhibit higher affective well-being compared with less active participants.

Conversely,

“When a participant exhibited higher AWB [affective well-being] than their own average, their subsequent PA [physical activity] was higher compared with assessments with lower prior AWB (within-person association), and on average, participants with higher AWB showed higher overall levels of PA compared with participants with lower AWB (between-person association).”

An individual participant data meta-analysis of how physical activity relates to affective well-being in daily life

Put concisely, the more physically active you are, the more upbeat you will feel, and the more upbeat you feel, the more physical activity you’ll do. It’s almost like we’re designed by Mother Nature to move our bodies around on a regular basis. Huh!!!!

The finding that “adults with a lower BMI reported higher valence [feeling well and content] after being more physically active than usual compared with adults with a higher BMI” is particularly interesting in the light of the research discussed above, which found that people became less active after starting to use GLP-1 agonists for weight loss. Under normal circumstances, slimmer people get more of a pick-me-up from exercise than the more well-upholstered. This stands to reason: exercise is likely to be less uncomfortable and more enjoyable if you’re not encumbered by excess fat. But if GLP-1 drugs squelch your dopamine signalling, you won’t reap this benefit of finding exercise more rewarding as you drop weight.

Here’s another finding that caught my eye:

“The data suggest that individuals exhibiting higher average negative affective states show stronger reductions in their momentary negative affective states after engaging in more PA than usual compared with individuals with low negative affective states (r = −0.13, 99.2% CI −0.23 to −0.04). For positive affective states, the data suggest that individuals exhibiting lower average positive affective states show stronger increases in their momentary positive affective states after engaging in more PA than usual compared with individuals with high positive affective states.”

An individual participant data meta-analysis of how physical activity relates to affective well-being in daily life

Translation: exercise is particularly good at busting negative emotions in those most prone to them, and likewise, is more effective at bolstering positive emotions in those who habitually experience them less often. Once again, if GLP-1 agonists squelch physical activity, they will rob users of these life-enhancing effects on their affective well-being.

Of course, if you’re taking a GLP-1 agonist drug, you could use this information to motivate you to exercise more, even if it feels less rewarding. But it’s tough to maintain that motivation to do something that you don’t feel you’re getting much out of, over the long term. And of all the nasty adverse effects of GLP-1 drugs, this one may well turn out to be the most impactful of all.

But hey, if you’re a sociopathic Big pHarma exec, that’s good news, right? Think of all the extra customers you’ll generate for your antidepressants!

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