Don’t let the sun go down on me

‘Sundowning’ describes a state of confusion in the elderly that develops in the late afternoon and lasts until sleep finally knits up the raveled sleeve. Disorientation may be accompanied by anxiety, agitation, aggression, pacing, ignoring directions, hallucinations. It signals progressive brain damage, and foreshadows the slide into dementia.

The most notorious sundowner of our time is Joe Biden. The arc of his decline runs eerily parallel to that of Leonid Brezhnev, whose dementia was equally concealed during the last years of his dying empire but who had been, unlike Joe, a war hero and an effective politician in his younger days. Lord Gaga is important not for who he is but for who he represents; growing numbers of boomers who, confused and agitated, are not going quietly into that dark night.

And it is not just the elderly whose brains are being damaged. Neurologic disorders are affecting an ever-increasing proportion of the human race, and have become the top global cause of illness and disability (1). If Dubito, ergo cogito, ergo sum is true, we are becoming less ourselves, I think.

Neurologic disorders include the dementias (Alzheimer’s, Lewy Body, Parkinsonian and vascular), stroke, epilepsy, nervous system cancers, the spectrum disorders and brain damage caused by exposure to neurotoxins such as lead. Then there are conditions affecting the peripheral nervous system such as diabetic and chemotherapy-induced peripheral neuropathy. Adding tension headache and migraine pushes neurologic conditions into the top spot.

These conditions all have different but partially overlapping sets of risk factors and all appear to be rising in frequency and/or severity, and/or occurring earlier in life, although the epidemiology of Lewy Body dementia is unclear. Cumulatively, they reveal that our nervous systems are under attack.

As the pharmaceutical model has not yet delivered cures for any of these conditions and nor, in my opinion, is it likely to (ie 2-4), we should be putting more emphasis on preventative measures. Better control at the population level of hypertension and hyperglycemia would pay dividends, and of course the medical profession recognizes this. They see this primarily through a pharmaceutical lens, and focus on better diagnosis and the more extensive use of medication rather than the modification of primary causes.

There are more profound, and more profoundly protective measures we could take. The modern diet, replete with ultra-processed foods (UPF’s), is key to most and perhaps all the modern epidemics.

By reducing our exposure to UPF’s, making better food choices and getting a little more exercise, we can largely protect ourselves from hypertension and hyperglycemia. Using standard pharmaconutritional counter-measures we can also minimize or neutralize chronic inflammatory stress, along with oxidative, carbamylative, glycative and dysbiotic stresses, and we can achieve all of these things safely and inexpensively.

Two examples of how this might help occur at the beginning and at the end of life, among the spectrum disorders and the dementias.

It bears repeating that autism is a relatively recently recognised condition. First described in 1943 (5), and considered to be very uncommon at that time, the latest CDC report cites a rising trend which now affects 1 child in 36, and 1 adult in 45 (6).

It is not clear whether these figures can be entirely trusted; social media and the current Western cult of victimhood promote self-diagnosis, and the bulk of information on platforms like TikTok is dubious at best (7). Nevertheless, I tend to believe that there has been a real increase because there is good evidence (in my view) for a pre-natal inflammatory environment playing a causative or contributory role (8, 9), and overwhelming evidence for wide-spread chronic inflammation caused by the modern exposome (ie 10).

If maternal inflammatory status is a significant contributory factor for a child developing a spectrum disorder, then not smoking during pregnancy, sticking to a simple, produce-based diet and maintaining body weight should make a considerable dent in the stats. A standard pharmaconutritional program would help too. It might even be enough to bring autism figures down to the 1940 baseline.

Next, consider dementia.

On the positive side, there is at least some epidemiological evidence that the incidence of dementia may be falling (11). This has been related by a U Cal group to the fact that our brains might be getting bigger and, by implication, better (12). But can this really be correct? Is size really the critical issue here?

Brain size, and specifically the number of brain cells in areas such as the cerebral cortices does indeed correlate with intelligence (ie 12, 13), but synaptic density and efficiency must also play a role; which might explain why the correlation between brain size and general intelligence (g) is rather weak.

Running counter to U Cal’s Panglossian thesis, there is evidence that overall intelligence may actually be falling (14-18), and a range of environmental and other predisposing factors which are predominantly negative.

The air pollution typical of the cities where most of us live increases the risk of dementia (19, 20), partly via vascular effects and particularly when combined with poor nutrition (21). Wildfire smokes seem especially likely to induce brain damage (22), and one has to wonder whether the high incidence of such fires contributes to the Californian mind-set …

Depression is associated with an increased risk of dementia (23), and appears to be becoming more prevalent (24, 25), particularly in the collective West (25). Ultra-processed foods are also linked to increased risk (26), and are becoming a larger part of our diet (27). Related to this is the increasing burden of diabetes, which confers considerable added risk (28), and the interlinked problems of cardiovascular disease (29), chronic kidney disease (30), chronic pain (31) and mid-life obesity (32), all of which are also on the rise (ie 33-35).

Classical nutritional issues play into this too. In yet another demonstration of the grossly inappropriate nature of the modern diet, iodine depletion and deficiency – which are not uncommon (36, 37) – are re-emerging in parts of the developed world (38). They are linked to shrinkage of the hippocampus (39), which is associated in turn with accelerated cognitive decline (40).

Returning for a moment to obesity, the relationship is not a linear one. A pattern of early weight gain followed by subsequent loss in later middle age appears to be associated with particularly increased risk (32, 41). This may reflect early obesity-driven neuro-inflammatory stress, followed by a phase of declining appetite in those entering the early stages of age-related cognitive decline.

Now that the West is moving into long-term economic downturn, falling nutritional standards and the growth of social disparity do not augur well. Living in the most disadvantaged neighborhoods is associated with measurably poorer brain health by the age of 45, apparent loss of cortical tissue and a 20% increased risk of dementia in later life (42).

As national and family structures fragment under the attack of neo-liberalism, and political opportunists plunge us into poverty and contemplate sending our children to war, our lives will undoubtedly include more social isolation, and more traumatic episodes. Each of these factors increases the risk of dementia, via inter alia neuroinflammatory stress (43, 44).

In those sent to the trenches, using (and being exposed to) modern weapons will increase risk (45-48), probably via physical (cavitation) stress (48) and oxidative phosphorylative stress (49). The industrial diet has already made us more vulnerable to physical trauma-related brain injury (50), so boys going into battle today are fragile in ways that their grand-fathers were not (51, 52).

Given that all the prevailing winds are in the wrong quarter, I think that the optimism of the U Cal scientists who found emerging patterns of bigger brains and less dementia, is misplaced. I see no real-world evidence for their argument in in the UK, for example, where dementia diagnoses are at an all-time high (53), none in California and even less in Washington DC.

Even if the U Cal data is true, it is not substantive. How to avoid dementia? Acquire a bigger brain. Possibly. But how to grow a bigger brain? Bueller?

A better education (54) and more sensory stimulation (55) might help to achieve this but only, I suspect, when combined with adequately supportive and non-neurotoxic nutrition (50, 56).

Mitochondrial health is an important part of this picture.

Lewy body dementia has long been a mystery, although the pathoaetiology is known to involve accumulation of mafolded versions of the intra-neuronal protein alpha-synuclein. This disrupts mitochondrial and other vital cellular functions, with failing energy production contributing to synaptic decay and eventually cell death (57).

New research shows that the incidence of Lewy body dementia is very significantly reduced in older men with benign prostatic hyperplasia, who had been treated with the alpha-1 blockers terazosin, doxazosin, or alfuzosin (58). It just so happens that these drugs increase glycolysis and mitochondrial ATP output (ie 59), effectively boosting (restoring) cellular energy formation.

This may be a more general neuro-protective mechanism. The alpha-1 blockers also appear to be helpful in Parkinson’s Disease (60, 61), which, like Lewy Body dementia, involves the accumulation of malfolded alpha-synuclein (57).

The hypothesis here is that as ageing neurones’ ability to generate energy declines, their metabolism skews and proteostasis degrades, allowing the accumulation of malfolded and therefore malfunctional proteins such as alpha-synuclein and beta-amyloid. These impair energy generation further, causing a vicious spiral down to cell death.

If this is true, then other drugs which improve cellular energetics should also show therapeutic benefits. Metformin is one such, and there is increasing evidence that low-dose metformin may indeed reduce the risk of neurodegenerative disease (62-65), although this is contested (66).

As my training as a pharmacologist leads me to focus on mechanism of action, I am predisposed to believe the metformin story. Jiaogulan, a non-pharmaceutical equivalent to Metformin (66), also appears to protect against the dementias (67-71). So do near-IR lasers, which improve cellular energetics via a different mechanism altogether but exert similarly neuro-protective effects (72-74) which are not affected by the time bias cited in (66) above.

If a Lewy body or Parkinson’s patient asked me, I might also suggest the fungal amino acid ergothioneine, which has demonstrable mito-protective properties (75, 76); and/or glyteine, the orally bioavailable precursor to gluthione (77).

As anxiety and depressive illness are linked to a higher risk of dementia, at least in part via chronic neuroinflammatory stress, non-pharmaceutical strategies that reduce the incidence of the affective disorders also seem like a good idea. Saffron comes to mind, and to this we could add the keto diet (78) and exercise (79), from walking to jogging and strength training.

(Having said that, it  may be that late-life anxiety is simply a prodromal symptom of PD).

Both the keto diet and exercise may act in part via anti-inflammatory mechanisms, and one could consider augmenting these approaches with a combinatorial antioxidant supplement.

Last, but not least, look after your gut.

There is emerging evidence that gut and brain work together to build resilience to stress (80), an approach which would be expected to reduce affective problems and, in the longer term, neurodegenerative disease. Impaired colonic epithelial barrier function seems to be involved in both Parkinsonism and Lewy Body dementia (81), making sustained endotoxaemia, neuroinflammation and dysbiotic-induced alpha-synuclein three likely links between dysbiosis and dementia (82, 83).

A more recently discovered putative link involves estrogen. Women are twice as likely to dement as men (84), a finding that has traditionally been ascribed to women’s longer life-span. A more interesting take on this is provided by new research in which the use of pure estrogen antagonists was associated with a significantly reduced risk of dementia (85). If this is true then putting prebiotics back into the diet to modify the estrobolome, leading to lower estrogen blood levels (86, 87), should be protective; and there is indeed evidence that this is the case (88).

Blended prebiotics are likely to produce the best outcome here, but for optimal results they should be integrated into a dietary and/or supplemental regime which also provides anti-inflammatory, antioxidant, anti-glycative and anti-carbonylative cover.

The pre-transitional diet did most of these things. Unfortunately for us the post-transitional, industrial diet does not. It adds insult to injury by providing excessive amounts of sugars and fats, a combination which leads directly to hippocampal damage (89), which is an important precursor to dementia.

This is why I have invested my own health prospects in an old-fashioned UPF-free diet, and top it up with the Health Protocol. According to the latest Lancet Commission Report, simple lifestyle choices could prevent up to 50% of cases of dementia (90). If they were bold and interventionist enough to incorporate a pharmaconutritional component, we could prevent many more.

Food can be either a slow poison, as it is for most consumers today, or the safest and most effective form of medicine. Are you ready to order?

Finally, a meditation on life, death and dementia from the metaphysicist Stuart Lee (91).

Next week: Shelf lives, expiry dates.

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