Time and Spice

As we pass through time, or as it passes through us, a series of changes accumulate which we call ageing. 

Superficial changes such as the progressive symptoms of chronic degenerative diseases can in many cases be prevented, and partially or completely reversed using inexpensive pharmaco-nutritional tools. 

Deeper delta such as the reduced expression of mRNA splicing factors, the loss of telomeric DNA, declining immune-surveillance, the lack of progenitor cells, the loss of proteostasis and the accumulation of senescent cells, seemed inaccessible. 

Until quite recently.

For anyone who left college more than 30 years ago, RNA splicing might just be the least familiar of these deep signs. It is incredibly exotic but it is also, now, biology 101.

For non-scientists, it is a stage in the DNA-RNA-protein sequence where RNA transcribed from DNA is edited before translation into protein can begin. It involves the cutting out of introns, genetic hot-spots which do not code for proteins but are more like switch points or punctuation marks; and the re-assembling of exons, those sections which do code for proteins. 

This editing process takes place in particles called spliceosomes, which are mostly located in the cell nucleus. It is essential for correct protein synthesis, and is aided and abetted by mRNA splicing factors which are tissue-specific, and influenced by the outside world via epigenetic factors (1). (Pending post ‘The Meth Lab’ goes into the epigenetic factors in more detail.)

Minor modifications in pre-mRNA splicing, facilitated by the different splicing factors in different tissues, allow the cell to build an extensive portfolio of proteins from a more limited number of genes. The best-known example of this is probably the single gene that codes for a structural protein (crystallin) in the lens and an enzymatic protein (LDH) in muscle (2).

Quality control of proteins in the cell (aka proteostasis) is critical for the functioning and survival of the cell. It involves the fine control of protein assembly, folding, monitoring and, when the protein has reached the end of its working life, dispatching it to a proteasome for breakdown and recycling. 

Faulty RNA splicing contributes to the synthesis of incorrectly built proteins, and the quality and quantity of splicing factors decline with age. This causes a progressive increase in faulty protein synthesis, the loss of proteostatic control, growing endoplasmic reticular stress and the beginning of the end of the cell’s productive life (3, 4). (See previous post, Know When to Fold ‘em).

The vast majority of cells then activate one of several possible suicide sequences, sacrificing themselves for the collective good. 

A few drift off into senescence, lingering on aimlessly but still consuming valuable resources, creating chronic inflammatory stress and contributing to inflammatory and degenerative pathology. A smaller number become cancerous, striking a Faustian bargain whereby the cell gains temporary immortality but the collective dies.

Most of these mini-Fausts fail. They are killed off by metabolic bottlenecks, immunosurveillance and/or the cancer-killing properties of an array of phytonutrients, aided and abetted by the omega 3 HUFA’s. Only a very small percentage of cancer cells survive and multiply to the point where they become clinically significant. 

The fact that around 30% of us now die from cancer, as opposed to 3-5% in pre-transitional societies (5, 6) and 1-3% in non-domestic animals (7), testifies to our disastrous diet and lifestyle. (Pending post ‘Peto’s Pet Paradox’ focuses on diet and cancer in other species). 

Back to the RNA splicing factors. Recent work stands received wisdom (and time) on its head, by showing that the age-related decline in splicing factors can be reversed by specific phytonutrients.

Polyphenols such as resveratrol and genistein can bind directly to DNA and RNA (8). At high doses they cause DNA damage and can induce apoptosis (ie 9), but at low doses they enhance DNA repair via hormetic mechanisms (10).

They also positively influence the splicing process (11-13). They appear to do so in part by restoring levels of specific RNA splicing factors (11-13), and have now been shown to rejuvenate senescent cells, with restoration of telomere length and the ability to replicate (13, 14). They also selectively kill those senescent cells that do not regenerate (14, 15).

These are profound anti-ageing and life-extending effects; but what causes senescence in the first place?

Cells have an array of responses to different degrees and types of stress ranging from positive adaptations at one end (generally induced by lower levels of stress), to death when stress is extreme. Just below the lethal threshold, very high levels of stress – such as those triggered by severe endoplasmic reticular stress, telomere loss, DNA damage and/or the beginning of cancerous change, can cause senescence (16).

Small numbers of senescent cells can be tolerated, but as their numbers increase the tissues and organs in which they are located become compromised. The cells express an array of pro-inflammatory compounds called the Senescence-Associated Secretory Profile or SASP. The SASP causes progressive tissue damage and is a significant driver of the ageing process (17, 18). Via SASP, senescent cells induce senescence in neighboring cells, and the spreading rot leads towards tissue and organ failure (19, 20).

Local injections of senescent cells into various tissues accelerate the age-related diseases (21, 22). Conversely, the elimination of senescent cells delays the onset of age-related pathology in neurodegenerative, cardiovascular and other pathologies, including cancers (23-24). 

Cancer becomes more likely as we age, at least in societies consuming a post-transitional diet.

The accumulation of senescent cells in aged tissues or xenograft models correlates with the incidence of cancer (25-27); while senolytic drugs (compounds which selectively kill senescent cells) delay tumor formation and reduce metastasis (24, 28, 29). 

Senolytic drugs are, therefore, starting to find many clinical applications. They target a number of well-defined key proteins involved in apoptosis such as Bcl-2, Bcl-X_L, p21, PI3K, AKT, FOXO4 and p53. But do we really need these drugs? The polyphenols, which are a good deal safer (they are in our foods after all), act at all of these same points (30-36).

It has been suggested that they may not be safe for general consumption, because in some pre-cancerous cells a shift into senescence is protective against cancer; and some anti-cancer treatments work by inducing senescence in cancer cells. However, these senescent cells must be cleared to avoid a chronic pro-tumorigenic state (37).

Furthermore, the same polyphenols which rejuvenate or kill senescent cells are also good at killing cancer cells, and/or inducing cell cycle arrest and/or redifferentiation (ie 38-41). In this way they provide an umbrella seno- and chemo-protective effect; one of the reasons why increased intakes of polyphenols within the dietary range are associated with better health (42, 43).

These same polyphenols also damp chronic inflammation (44), and are involved in the fine control of many enzymatically controlled reactions (44, 45).  They protect, in multiple ways, against metabolic, cardiovascular, neurodegenerative and oncological diseases (37, 46, 47). In short, these ‘anti-nutrients’ as they were once called, are as important to our short and long-term health as any established vitamin or trace element.

We are thoroughly adapted to the near-constant presence of polyphenols in our bodies as modifiers / modulators. Their polyfunctional profiles trace a map of our evolutionary and dietary origins, a map on which the borders between the animal and plant kingdoms are long and complex, with very many checkpoints. 

Neglecting those borders incurs a heavy penalty. 

Over the last few decades, as our understanding of the significance of the polyphenols and other phytonutrients has developed, Big Phood’s irresponsibility in removing them from our diet has imperceptibly morphed into criminal irresponsibility. Ultra-processed food is the new tobacco. Post-transitional public health illustrates the madness of the modern diet. The political classes take their money and drag their feet.

The harm done by removing polyphenols from our diet is compounded by the addition of huge amounts of empty, pro-inflammatory calories in plant oils and sugars, to provide cheap and infantilized flavour profiles (48, 49). These in turn drive the epidemics of obesity, non-alcoholic liver disease and all the other ‘diseases of civilization’. 

In a final turn of the screw obesity, metabolic syndrome and diabetes increase the senescent cell load (50-53). This provides yet another mechanism linking the ultra-processed diet with rising BMI, accelerated ageing, declining health and life expectancy, and increased anxiety and unhappiness (54).

The utter idiocy of Covid lockdowns manifests inter alia in the near 100% rise in obesity and types 1 and 2 diabetes in children (55). There will be blood, because outside the Dumb and Dumberer world of politics, everything connects. Time may not be speeding up but one of the ways in which we experience it – the ageing process – certainly is.  

What can a concerned person do?

Selectively killing senescent cells in obese mice restores metabolic parameters (56) – so here is one anti-ageing role for the polyphenols. Conversely, caloric restriction reduces the burden of senescent cells (57), and the polyphenols, by acting as caloric-restriction mimetics (58), are likely acting here also. As mentioned above, the polyphenols are also good at killing senescent cell (ie 59).

Increasing our intake of polyphenols provides a set of keys, therefore, to modifying deep delta. 

With the exception of the few amphiphilic polyphenols (such as olive and marine algal polyphenols), these compounds are not stored in the body for long. They are regarded as foreign molecules and rapidly metabolized and excreted, so we should plan on consuming polyphenols on a daily basis. 

Polyphenols are not, however, the whole story.

Senescent cells are antigenic, and are aggressively picked off by the immune system. As we get older the immune system tends to become less effective, which is another reason why senescent cells accumulate as the decades pass (60).

The most effective method known of enhancing immune-surveillance is exercise (61-64). Much or all of this effect is mediated via AMP-kinase (65, 66), and is therefore theoretically achieved with phytonutrients derived from ie Gynostemma pentaphyllum (67), marketed as ActivAmp. In support of this idea, there is emerging evidence that physical exercise reduces numbers of senescent cells (68).

Exercise and/or ActivAMP, plus frequent doses of a range of polyphenols, will help to reduce the burden of senescent cells and will also improve immune function. This should provide significant anti-ageing benefits. Adding an omega 3 / amphiphile polyphenol combination to reduce the inflammatory effects of SASP (69-71), and inflammageing in general, should push the clock even further back.

In practical terms cut out the ultra-processed foods, and add spice. 

Spices are the most concentrated dietary sources of polyphenols (72), and the curcuminoids in turmeric are among the best documented up-regulators of RNA splicing factors (73-75). They are also senolytics (76, 77), and will do both of these things if you manage to achieve meaningful plasma levels of these actives. Currently, HydroCurc is one of the best ways of doing this (78).

Just one last slice of deep delta.

There is evidence that along with the accumulation of senescent cells, ageing of tissues and organs is also driven by a growing scarcity of new progenitor (or precursor) cells (ie 79, 80), which are needed to replace those which have died or become senescent.

We carry a reserve of precursor (stem) cells which act as a repair kit. These stem cells are stored in the marrow of our long bones but as we age they become more reluctant to leave their bunker, becoming less available just when we need them most. Fucoidans, polysulphated oligosaccharides from brown seaweeds, release them into the circulation and put them back to work (81).

It seems logical to combine fucoidans with the right polyphenols, and many of us are already in the throes of self-experimentation. Based on blue zone data, the optimal long-term dietary intake of polyphenols is approximately ten times higher than the average amounts consumed today (ie 40). If you intend to self-administer higher doses of polyphenols, this should be restricted in my view to a semi-acute window of no more than 2 weeks.

Finally, senolysis is not the only road ahead. Senescent cells can be re-programmed and partially rejuvenated using a variant of the Yamanaka approach (82-84). These exciting research findings are consistent with the reported benefits of heterochronic transfusion (ie 85), which may work in a broadly similar way.

Ask about deferred payment schemes at your local blood bank.  

Next week: Old salt, and how the food industry fights dirty.

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