The ageing process incorporates intrinsic and extrinsic components. This is obvious in skin, where the intrinsic ageing that shows in sun-protected areas presents very differently to the combined intrinsic and extrinsic ageing that affects areas exposed to sunlight. Intrinsically aged skin is smooth, thin and transparent; extrinsically aged skin is typically rough and wrinkled.
Extrinsic ageing is reckoned to account for up to 80% of the overall ageing process, depending on your latitude, attitude, lifestyle and diet. The photo shows my friend Nick, a gentle soul who is homeless, an alcoholic, a diabetic, a smoker and lives in the sub-tropics. He is 11 years younger than me, but has all the major extrinsic factors stacked against him.
The dual ageing process is less obvious in other tissues, but they experience intrinsic and extrinsic ageing too.
When intrinsic rates of cartilage formation slow in older age the progressive loss of cartilage mass and function affects all the joints in the body, but is generally noticed first in hips and knees where the extrinsic factor of increased body weight causes additional and repetitive reperfusion injury (1-4). When bone moves through time towards osteopenia and then osteoporosis the entire skeleton is intrinsically affected. All bones – including the skull – become more fragile, but the femoral neck, vertebrae and wrists are most likely to fracture. I’m stretching a point here, but this is probably due to extrinsic factors including abrupt changes in torque, load and/or loading angle.
In all tissues, intrinsic ageing is inevitably exacerbated today by the extrinsic ageing factors chronic inflammatory stress, dysbiosis, type B malnutrition and immunological senescence. These can legitimately be regarded as extrinsic because they are generally caused by dietary and lifestyle factors; but modern medicine does not take this sufficiently into account, partly for historical reasons.
The progressive losses of tissues such as cartilage or bone are classified as chronic non-communicable degenerative diseases, along with cardiovascular disease, neurodegenerative disease and many other health conditions.
For most of the 20th century, such conditions were considered to be entropic, partly because of the failure of pharmaceuticals to do anything to modify the course of these diseases. This created a mood of medical fatalism which influences medical thinking to this day. Life, however, is intrinsically anti-entropic; and it is more productive to view these conditions through the lens of tissue economics. Cartilage and bone provide two examples.
During the first two decades or so of life, bones and epiphyseal cartilage plates grow in size. During the 3rd and 4th decades these tissues are unchanging, but thereafter they start on a slow and continuing decline until pain and disability surfaces, or a catastrophic structural failure occurs.
But these are living tissues, after all, and like all living tissues, bone and cartilage are dynamic. They are continually being broken down and regenerated. During those first two decades the process of bone or cartilage formation outstrips the rates of tissue erosion, and there is a net gain of functional tissue. During the 3rd and 4th decades rates of formation slow and rates of breakdown rise, until they are in balance. The apparent stasis of the bones and joints during those years conceals a dynamic equilibrium. In the 5th and subsequent decades, rates of tissue formation slow and rates of breakdown rise. This leads to a slow and progressive loss of functional tissue until redundancy is outstripped and, late in the course of the ‘degenerative disease’, clinical symptoms emerge.
The main hallmarks of ageing are considered to be genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. For most people, however, the bulk of the symptomatology of ageing can be attributed to a slowly progressing loss of the extra-cellular matrix (ECM), a process rather like the gradual fraying of fabric. This is what causes the gradual disintegration and loss of functional tissue.
Fraying to death might sound like a Chuck Jones scenario, but this is an optimistic view of ageing because the two most important factors that determine ECM economics are extrinsic, and highly malleable. The breakdown of ECM is predominantly driven by chronic inflammation and the rate of ECM regeneration largely depends on the availability of a range of vitamins, trace elements and other co-factors. The modern diet, which causes chronic inflammation and Type B malnutrition, is therefore a major cause of accelerated ageing. The extrinsic part of ageing can, therefore, be rectified.
The ageing of skin falls exactly into this category. The same ECM that provides form, function and compressive strength to cartilage and bone provides structure, thickness, elasticity and hydration capacity to skin. The development of lines and wrinkles, the thinning and the loss of tensile strength, elasticity and hydration are all largely attributable to the loss of extracellular matrix in the dermis and epidermis. As the age-related losses of ECM in cartilage and bone are considered to be degenerative diseases, we should logically classify ageing of the skin as a degenerative disease also. ‘Dermatoporosis’ sounds about right.
A made-up name, you say? Of course it is, just like all the rest. Bill McElligot, the truck driver whose face was famously damaged on one side by chronic sun exposure (5), developed unilateral heliodermatitis after the medics got involved …
Repositioning skin ageing as a degenerative disease opens up new therapeutic possibilities, and the possibility of slowing and even turning back the clock by reducing extrinsic ageing with pharmaconutritional tools. But in order to fashion effective tools, we need to know the mechanics.
Extrinsic ageing of skin – the mechanisms
Extrinsic ageing of skin was first reported at the end of the 19th century, when it was described as ‘farmer’s skin’ or ‘sailor’s skin’. There was an awareness that sun exposure was an ageing accelerant, and we now know that UVA (315–400 nm), the major component of sunlight, is the main villain. UVB (280–315 nm) has a shorter wavelength and cannot penetrate the skin as deeply, but carries more energy and is more of a risk for skin cancer.
UV radiation induces oxidative and inflammatory stress, as does cigarette smoke, and these stresses lead eventually, via free radical-mediated cell damage to lysosomal release of a cascade of cathepsins, proteases and matrix metallo-proteases (6, 7). These enzymes degrade the fibers of the extra-cellular matrix including the collagens (8, 9), and elastin (10). This accelerates skin ageing; as does diabetes.
Diabetes causes degradation and accelerated breakdown of the ECM via random and non-enzymatic glycation reactions, whereby proteins in the ECM such as collagen and elastin are chemically altered. This drive the inflammatory sequence via the AGE/RAGE interaction; and at the same time modifies the ECM-building activity of the fibroblasts (11, 12), leading to the deleterious skin changes seen in diabetic patients. The process of glycation can be inhibited in vivo by various polyphenols (ie 13), but these are sadly lacking in the modern, highly glycaemic diet (14, 15). Ingestion of excessive amounts of AGE compounds in ultra-processed (15) and other foods cooked at high temperature would be expected to exert a similar ECM-damaging effect.
The growth of new ECM depends on the presence of multiple co-factors including vitamins C and B6, the trace elements copper, zinc, iron and manganese; and the maintenance of existing ECM requires a variety of vitamins (A, C, E) and phytonutrients including carotenoids and polyphenols (16), probably best used in combination (17).
The modern diet is intrinsically pro-inflammatory (15, 18, 19), obesogenic and diabetogenic (20), and at the same time depleted in many of the above co-factors.
Logically therefore, it must accelerate ECM breakdown, reduce ECM maintenance and impede ECM regeneration; and drive chronic degeneration of the skin aka skin ageing. As extrinsic ageing accounts for the majority of skin ageing, nutritional improvements should have a major impact on appearance.
This has been studied by many scientists in many research centres, looking for that Dorian Gray sweet spot – and there is an international consensus that phytonutrients are key (21, 22). Ex-vivo, pre-clinical and clinical studies have shown positive effects with polyphenols derived from grape, cocoa, tea, mushrooms, grapes, apples, oranges, strawberries and walnuts (23-32); and carotenoids derived from red peppers, marigolds and tomatoes (33-38). You don’t even need to buy over-priced supplements, tomato paste will do just as well (37). Fish oil helps too (39), and is best combined with lipophile polyphenols. Vitamins C and E play supportive roles.
We decided to extend this work, and developed a pharmaconutritional program which slowed ECM breakdown, enhanced ECM maintenance and accelerated ECM regeneration, all at the same time. We ran an in-house trial of a multiple-component skin care regime based on this premise. Chronic inflammatory stress in our subjects was damped using an orally ingested omega 3 HUFA / lipophile polyphenol blend, and all the co-factors required to support ECM formation were supplied in tablet form. A topical cream was used containing UV-blockers, anti-inflammatory agents and a dual fibroblast stimulatory package comprising solubilised 1-3, 1-6 beta glucans (ie 40), and the more familiar copper peptides.
Skin elasticity increased by 28% in 60 days, measured using industry standard Courage and Khazaka test systems. This represented substantial regeneration of the ECM in the dermis and epidermis, and constituted a very significant anti-ageing effect. The subjects also showed marked wrinkle reduction and enhanced skin smoothness and bloom, which paralleled the elasticity data. I subsequently came across a second smaller scale trial, conducted entirely independently, which showed reduced pore size. This was a total surprise, because it indicated improvements not only at the molecular and micro-structural level but at structural and organisational levels also.
Polyphenols and carotenoids are phytoalexins, compounds produced by plants to defend themselves against pathogens, predators and ultraviolet radiation. As the year progresses and solar radiation and the energy content of the plant increase, levels of the phytoalexins increase also as part of the ripening process. Humans were hunters and gatherers, and our intakes of these phytoalexins increased in parallel, as our diet followed the same solar path. As it did, we gained the same protection from solar radiation as the plants; we were like hermit crabs, taking on a shell discarded by another species and making it our own. We were not designed to fear the sun or to be nocturnal. We were protected by a diet which packed our skins with natural UV-filters, antioxidants and anti-inflammatory agents.
The industrialization of food is relatively new and as recently as the 19th century, eating seasonally was both necessary and a part of the folk wisdom. British men and women going out to ‘assume the burden of Empire’ were advised to eat more fruits and nuts, because someone, somewhere had noticed that this afforded a degree of protection against sunburn (41).
The skin-protective phytoalexins are still present in our food today, but at much lower levels. Today’s ultra-processed foods leave us depleted and vulnerable, dependent on sunscreens and scared to death of skin cancer. There are more negative dietary factors in our diet also; a high fat intake plus alcohol increases inflammatory stress and reduces ECM regeneration, and is pro-ageing (42). The pathogenic omega 6:3 ratio and high levels of AGE and ALE compounds in ultra-processed foods are at least as damaging.
We traded berries for botox and a scalpel. We exchanged a walk-on part in the war for a lead role in an e-cage.
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