Chronic stress slows the brain down as we age. There are various kinds of chronic stress, and new evidence indicates that brain functions can be restored by identifying which kind of stress is involved, and blocking it. New drugs can do this; but so can old nutrients.

Long ago, children, when the world was young, proteins were broadly classified as either enzymatic or structural. Then came protein messengers, transporters and chaperones, with all three categories partially overlapping. Then it started to get complicated. 

There are several different kinds of chaperones. 

One sub-set of chaperones includes proteins such as poly(rC)-binding proteins (PCBP)-1 and -2 and the ferritins which bind, defuse and store or transport potentially destructive items such as iron. Haemoglobin could be defined as a chaperone / transporter protein for oxygen, but like many proteins it is multi-functional and is a chaperone / transporter for iron too.

There are two totally different sub-sets of proteins called protein-folding chaperones, and chaperonins. Most of these are heat shock proteins, members of a fascinating group of stress responders / adaptors called alarmins which I will return to in a future post, and they are also quality controllers. 

Newly formed proteins entering the endoplasmic reticulum must be correctly folded to achieve their final form and function. This is a complex procedure with a failure rate of over 80% (1-3). Malfolded and therefore dysfunctional proteins are potentially extremely destructive; chaperones assist correct folding and unfolding, while chaperonins identify damaged proteins and either repair them or – if the damage is too great – take them for recycling in the nearest proteasome (1-3). 

In other words, the chaperones and chaperonins are involved in instructing the cell what to throw away and what to keep.

They maintain intracellular protein quality control, otherwise known as proteostasis. This is critical; too many malfolded proteins accumulating in the endoplasmic reticulum create endoplasmic reticular stress (ESR), which if unchecked will eventually trigger apotosis (4-6).  But they do not work alone.

Lately a new breed of microproteins has emerged. In protein terms, they are tiny. They look like polypeptides – structurally they are polypeptides – but unlike most biologically active polypeptides such as the hormone ACTH which are cleaved from larger proteins, micro-proteins are built de novo as small, fully functional units.

Microproteins were previously overlooked because genome analysis excluded sections of DNA less than 100 codons in length (coding for 100 amino acids), as such sections were thought to be too small to be genes. Now these micro-proteins are being termed the dark matter of the proteome, and they are one of the hottest areas in protein research. 

They may be involved in many and perhaps all metabolic processes. There may be hundreds or even thousands of them, and they are difficult to identify let alone measure because many of them seem to be very short-lived, so many of their actions may be very local and very transient. They have been shown to impact on the immune system, muscular and mitochondrial function, RNA recycling, and heaven knows what else. And their mechanisms of action are fascinating.

Being so small they probably don’t fold, so they are probably not enzymes. But because they are so small they have the ability to align with similar amino acid sequences in larger proteins, subtly modifying their shape and function. By enabling minor modifications to protein structure, they act like even finer-tune versions of the already fine-tune chaperones and chaperonins. 

Some microproteins found in spider and scorpion venom are potent blockers of ion channels, which makes them potent neurotoxins – and, potentially, analgesics (7). One microprotein, derived from the venom of the deathstalker scorpion, has such high affinity for cancer cells that it is being used as a cancer marker and may eventually be used to deliver anti-cancer drugs in vivo. A few others have been synthesized and are finding applications as novel insecticides.

All of this is changing our understanding of what proteins are.

DNA may be the blueprint and proteins may be the end-products but they are also the assembly lines, the workers who operate those lines, the maintenance team, the foremen, the managers and the Executive Directors. There are tens of thousands of human proteins and up to a thousand micro-proteins, and even tiny rearrangements of these vital molecules can have knock-on effects on our health, generally culminating in disease and death. 

All of this was floating around in my ageing head when I came across a fascinating paper on an ISRIB which reversed age-related cognitive decline in elderly mice by stimulating hippocampal neurons to make new and better connections, all within 72 hours (8). According to Peter Walter, one of the authors, ‘This suggests that the aged brain has not permanently lost cognitive capacities but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress. Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.’

An ISRIB is a compound – in this case a drug – which inhibits the Integrated Stress Response (ISR). The ISR is something that cells do when they are affected by major stressors. These include extrinsic stressors such as viral infection, hypoxia, heat and nutrient deprivation and/or excess; and intrinsic stressors such as cancerous mutations and endoplasmic reticulum stress (ERS). 

The ISR turns down global protein synthesis, which is designed to kill the virally infected or cancerous cell. If the stressor is in the heat / hypoxia / nutrient group, however, the ISR effectively puts the cell into dark mode until the hard times are over. This is a very subtle response, and still allows the translation of a select few mRNA’s to aid cell recovery once the threat has passed (9, 10).

To summarise, an acute and strong ISR to a virus or cancer cell is an adaptive and protective response, and if it neutralizes the threat (ie kills the cancer cell or virally infected cell), that is the end of it. If the stressor is heat, hypoxia or nutrient-related, once the stressor has passed the cell can then start to recover and return to homeostatic health. But if the stressor is sustained a low-grade ISR continues to smolder away, causing long-term impairment locally and ultimately systemically. 

This is analogous to inflammation. Acute inflammatory responses to a pathogen or to tissue damage are entirely adaptive, and essential. Chronic inflammation, on the other hand, causes local and eventually systemic damage if left unchecked for long enough. Like chronic inflammation, chronic ISR is triggered by the modern diet. More accurately, the metabolic imbalances caused by the modern diet cause chronic inflammation and endoplasmic reticulum stress which feed on each other and drive low-grade, chronic ISR (11-13). And this is where protein folding comes back in. 

When metabolism is sufficiently skewed the accuracy of protein folding in the endoplasmic reticulum falls below the already low base-line of 20%, and accumulation of misfolded or unfolded proteins in the endoplasmic reticulum then triggers ERS (14-16). This activates the ISR, leading to a down-regulation of protein synthesis, and at the same time increasing protein folding and the degradation of unfolded proteins (17, 18). 

If the extrinsic or intrinsic stressor is neutralized the ISR switches off, levels of misfolded proteins in the endoplasmic reticulum return to normal and the cell returns to proteostasis, homeostasis and health. If recovery systems fail and unfolded and misfolded proteins continue to accumulate, the cell enters the apoptosis pathway and self-terminates (19, 20). 

If stressors continue at low level, however, which is what happens if you persist in eating a modern, ultra-processed diet, chronic ERS leading to chronic ISR will lead to longer-term cellular problems and eventually emerge as a clinically recognisable form of dysfunction or disease (13).

Back to the magical ISRIB drug that reverses age-related cognitive decline (8). The ISRIB inhibits the ISR directly, but we can use other tools to achieve the same end-effect. There are specific nutrients that switch ERS off, thus removing one of the main drivers of chronic ISR; and it is no coincidence that these nutrients duplicate the effects of an ISRIB and improve cognition in ageing brains.

ERS is induced inter alia by excessive glucose load, which causes inflammation. This can be prevented by polyphenols such as epigallocatechin3gallate (21, 22) which is derived from tea, emodin (20) derived from buckthorn and rhubarb, and mangostin (24), derived from mango. 

These findings refer to the rescue actions of polyphenols in podocytes but are almost certainly more general; EGCG is also capable of reducing ERS in various models of neurological disease (25-28), and the polyphenols in general reduce ERS in many other tissues (ie 29, 30). In cancer cells, however, they trigger cell death by increasing ESR (31). You gotta love those polyphenols!

The omega 3 fatty acids are relevant too. ERS induced by a high-fat diet, which also causes inflammation, is inhibited by the parent omega 3 alpha-linoleic acid (32), and the longer chain omega 3’s EPA and DHA appear to have similarly protective properties (33). So it’s the omega 3 / polyphenol combo, yet again …

The modern diet combines an excessive glycemic load with polyphenol and omega 3 deficiency, and is therefore prone to causing long-term ERS, loss of proteostasis and chronic ISR. The documented ability of polyphenols and omega 3’s to reduce ERS (and inflammation in general) makes them prime candidates for improving cognitive function, and much else besides.

The polyphenols in cocoa, for example, improve cognition in humans (34). Investigations have so far focused on improvements in cerebral blood flow which could impact ISR directly, but given what we know of the impact of ECGC, emodin and mangostin on ERS, it seems very likely that cocoa works here too. 

Other polyphenols have been shown to enhance cognition in elderly mice (35-37) if given long-term; and while this is a long-term effect as opposed to the more immediate effects of an ISRIB drug, consuming a high-polyphenol diet is a more natural and likely safer strategy.

I am not implying that synthetic ISRIBs are inherently dangerous. One has been shown to inhibit damaging low-level, chronic ISR activity but still leave the cell able to mount an acute ISR when it is needed to deal with an immediate threat (38). But their long-term effects are unknown (all drugs have side effects), and food-derived ISRIB’s such as polyphenols are intrinsically safer. 

A polyphenol-rich diet tastes better too, and there is good evidence that some of the health benefits of these phytonutrients are exerted via the positive modulation of proteostasis (39). Adding a low-carb diet (40) and minimizing contact with the weed-killer glyphosate (41, 42) will likely produce further gains.

Finally, the polyphenols have home-team advantage. As mentioned above, polyphenols can cause apoptosis in cancer cells by up-regulating ERS (31, 42), possibly because such cells are already experiencing strong ISR. This dual effect, namely supporting healthy calls and killing cancer cells (43-48), is a well-known property of the polyphenols and is exactly what the doctor would have ordered. If only he or she had studied pharmaconutrition.

I’m no Kenny Rogers fan, but he had his finger on the pulse when he sang –

‘Every gambler knows that the secret to survivin’
Is knowin’ what to throw away and knowin’ what to keep,
‘Cause every hand’s a winner and every hand’s a loser
And the best that you can hope for is to die in your sleep.”

This is a guest post. Any opinions expressed are the writer’s own.

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