Dry Spell

A recent research paper (1) which linked better hydration to extended health and slower biological ageing, generated a lot of publicity. The lay press overflowed with puff pieces claiming that drinking more water was the simplest and cheapest road to a longer and healthier life. Could it really be so simple?

The story is not a new one. The current paper was derived from the US Atherosclerosis Risk in Communities (ARIC) study, and was the second in a series of similar results published by the same research group, but utilising an extended data set (2). A different research team, working with the National Health and Nutrition Examination Survey (NHANES) and the 2015 public-linked NCHS mortality files, had published similar findings a year previously (3). 

Neither is the story universally agreed on. An earlier paper, based on NHANES 1988-1994 and 1999-2004 (4), found no significant correlation between water intake and mortality at all.

All of these large studies have methodological weaknesses.

The first and second studies, which used the seemingly robust probe of serum sodium levels, measured these on only two occasions three years apart. The third and fourth studies relied on water intake reports, which are not always consistent. Do you report what happened, what you can remember of what happened, what you think you remember of what happened, or what you think will show you in the best light?

Consider the rather more controlled pre-clinical world of the laboratory mouse, where water intakes are measured scrupulously and every whiskery life ends with an autopsy.

In mice, sustained water restriction accelerates multiple degenerative syndromes and shortens lifespan by 20 to 25% (5). In human terms, this equates to losing approximately 15 years of life. Given that humans with high blood sodium apparently show a similarly increased incidence of chronic degenerative diseases (2) and probably, therefore, a reduced life expectancy (1-4), the data appear rather convergent. 

Over-salted individuals also have elevated markers of inflammation and coagulation (2). These processes are interlinked and mutually self-reinforcing (6, 7) – and form one end of a potentially interesting thread.

While raised coagulation markers boost the risk of vascular disease, chronic inflammation is a driver of multiple pathologies. It is worth trying to tease out the links between water shortage and inflammation, so let’s follow that thread.

Thanks to the wonders of the world-wide web, we know that inflammatory signalling increases in the kidneys of dehydrated camels (8). Closer to home, the same thing occurs in dehydrated (ex vivo) human skin via up-regulation of sodium-dependent COX-2 and subsequent increased formation of the pro-inflammatory prostaglandin PGE2 (9).

The degree of scarring after injury is increased by inflammation (10), which is why keeping wounds hydrated and thus less inflamed, is critical for reducing excessive scar formation (11). As PGE2 exerts a wide range of biological effects associated with inflammation and cancer (12), it also begins to explain how sustained hypohydration could eventually lead to a range of degenerative clinical problems. 

This thread, however, has more than one strand.  In addition to boosting COX-2, hypohydration also triggers ROS signalling and cellular senescence, at least ex vivo (13), so here are two more ways in which being under-hydrated creates chronic inflammatory stress. And there is a fourth very plausible mechanism involving carbamylation.

Carbamylation is a bit like glycation, in that it denatures proteins in the body so that they become dysfunctional. Instead of sugars it involves isocyanic acid, which is produced in the body from urea. Hypohydration causes increased plasma urea levels and therefore increased protein denaturation, which is profoundly linked to ageing (14-16). 

It is all starting to look cut and – sorry – dried.

But now things get a little more complicated.

Being under-hydrated apparently drives ageing, but there is a reverse gear; ageing causes under-hydration. This occurs via two distinct mechanisms.

Ageing kidneys lose their ability to form concentrated urine (17), which means that older folk lose more fluid. At the same time, they drink less. Thirst is sensed in the lamina terminalis in the hypothalamus. Possibly due to hypothalamic mitochondrial decay (18), ageing brains become less able to recognize thirst and their owners are less likely to drink appropriate amounts of fluid (19). For these two reasons, underhydration is very prevalent in the elderly (ie 20, 21). 

So here we have a chicken and egg conundrum. Does dehydration drive unsuccessful ageing, does unsuccessful ageing cause dehydration, or do they run hand in hand?

There is evidence that in vestigial groups, who live an arguably more natural lifestyle, the ageing kidney does not lose its ability to form concentrated urine (22) and the ageing brain does not lose as much of its functionality (23). My hypothesis would therefore be that vestigials are less likely than industrialized folk to dry out as they get older, and if under-hydration really does drive the ageing process, they should experience less chronic inflammation and age more successfully than we do.

The answer, however, is not clear-cut. Vestigials are less prone to degenerative diseases than we are, but are they better hydrated? I could find no clear data to support or refute this idea. 

Do they have less chronic inflammation? Yes, and no. Some vestigial groups have relatively lower levels of inflammatory markers than we do while others have raised levels (24), likely due to parasitic infections and to living in forested areas. This last might seem a stretch but ‘forest bathing’, aka spending long periods of time in forests, has been shown by Japanese and Korean scientists to elevate inflammatory markers, presumably due to exposure to inhaled phytobiotics (25, 26).

The fact that all these vestigial groups are more protected from degenerative disease than we are may therefore have less to do with inflammatory stress, and more to do with their higher levels of physical activity and fiber intakes, and lower levels of obesity and insulin resistance (27). Sadly, these favorable vestigial conditions are being rapidly degraded by an invading rabble of Western industrial foods.

The vestigial diet and lifestyle differ from ours in so many ways that it would be rash to try to select any one variable above the others, so let’s take a different tack. The hypothesis that under-hydration speeds the ageing process by driving chronic inflammation could be tested simply and quite rigorously by improving hydration in a group of elderly subjects for a week or so, and measuring their inflammatory markers. 

The elderly would make good test subjects for this kind of intervention because they are significantly more prone to chronic inflammation than younger subjects (28). This is thought to be due to a combination of increased adiposity and periodontal disease, dysbiosis, innate immune dysregulation, reduced physical activity and accumulation of senescent cells, but under-hydration may factor in here too.

There are not much data. One small study suggests that hypohydration may increase the perception of pain (29), and another indicates that aggressive hydration speeds the resolution of mild acute pancreatitis (30). Unfortunately, while these findings suggest that better hydration might reduce inflammation, there were not enough elderly subjects and not enough probes to answer the question convincingly.

Any proposed study would have to be carefully controlled.

Increasing fiber intake shifts the balance of the colonic microbiota towards gram positive species, and reduces inflammation in the elderly (31) as it does in younger subjects (32, 33).

The proposed test would therefore have to control carefully for fiber intake, and subsequent work might look at the combination of improved hydration and supplemental prebiotic fibers. 

Might the improvements be additive, or even supra-additive? Might this translate into clinical benefits and end-points? I suspect it would, and if so, hydration plus blended fibers would be an inexpensive and safe way of extending health further into old age. 

To achieve further gains consider the omega 3 HUFA’s, and COX-2. As described above, COX-2 is central to the regulation of prostaglandins, is activated by hypohydration (9) and contributes to inflammageing via inter alia the pro-inflammatory prostaglandin PEG-2. 

COX-2 forms PGE2 from its precursor, the omega 6 HUFA arachidonic acid. Excessive PGE2 production could logically be countered by a combination of omega 3 HUFA’s and amphiphile polyphenols. Lowering the 6:3 ratio of HUFA’s in cell membranes leads to a more anti-inflammatory profile of prostaglandins (and other lipid mediators), while the olive polyphenols exert parallel and complimentary effects (ie 34-37).

More fluid, fibers, omega 3 fatty acids and olive polyphenols sounds like a recapitulation of key aspects of the Mediterranean diet. A dish of ratatouille, which is delicious and easy to prepare, would be a culinary step in the right direction – and is the sort of food that encourages hydration³⁸. Wash it down with a couple of glasses of sangria, and/or a jug of cool water.

Slainthe!

Next week: Paddle your own Keanu: The Matrix Reloaded.

References

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