D-Glucosamine as an Example of Calorie Restriction Mimetic Research

While destined to be a deserted sideline of longevity science at some point in the years ahead, research into calorie restriction mimetic drugs is presently in its heyday. Calorie restriction with optimal nutrition slows aging and extends life in near every species tested to date, though the shorter the natural life span of the species the greater the effect. A calorie restricted mouse can live 40% longer in excellent health, but that certainly isn't the case for humans - we'd have noticed an effect that large long ago. This is interesting, because the short-term effects on metabolism and markers of health are similarly large and beneficial in both species. Nonetheless, the consensus in the research community expects the effects of calorie restriction on human life span to be at the most in the ballpark of a 5% increase. The effects on health are much more impressive, however: if calorie restriction were a drug, it would dwarf the sales of any other pharmaceutical created to date, and deservedly so.

So if this is so great, why is it going to be a backwater? Because the objective of a calorie restriction mimetic drug is, as the name suggests, to mimic the metabolic response to calorie restriction - to produce at least some of the same health benefits. A perfect mimetic would result in the same outcome as practicing calorie restriction. But that means a mere boost to health and life that is large in comparison to doing nothing, but is tiny on the scale of what is possible through future medical science. We are entering the era of rejuvenation biotechnology, in which researchers are even today working on the foundations of ways to reverse the cellular and molecular damage that causes degenerative aging. That is the road to indefinite health, completely prevention of age-related disease, and a youth that lasts for as long as you want it to. It won't take much of that for the current fad of drug development aimed at slightly slowing down aging to wither away in favor of the obviously better line of business.

Nonetheless, much - arguably most - of the members of the comparatively small research community interested in treating aging are working away on this backwater to be. It is the mainstream flavor of today, just as the (probably only marginally better) mainstream flavor of tomorrow will involve genetic studies of aging and longevity. The disruption of treating aging as damage and working to repair it is under way with the advent of organizations like the SENS Research Foundation, but has a fair way to go yet before it takes over the mainstream.

The open access paper linked below gives a very good feel for the present state of calorie restriction mimetic research. There are a lot of compounds that seem promising, and researchers are engaged in tying their effects back to the growing knowledge of the puzzle of interrelated proteins and genes that make up the highly flexible operation of metabolism. For most this is the primary goal: not the generation of therapies, but the use of calorie restriction and ways to imperfectly recreate its effects as tools to understand the way in which metabolism determines the pace of aging, all the way down to the most fundamental interactions between proteins in cells. This is a very long-term project. The research community will have effectively cured aging long before the whole intricate dance of its progression is completely understood down to the lowest levels, or at least this will happen if all goes well in the repair strategy field.

All that said, the research into metabolism and aging is interesting and worth reading. It just isn't the road to human longevity in any practical, useful to those of us reading this today sense.

D-Glucosamine supplementation extends life span of nematodes and of ageing mice

D-Glucosamine (GlcN) is being widely used to prevent and treat osteoarthritis in humans and, according to a number of clinical studies, may be effective in this regard. However, mounting evidence suggests that GlcN may be ineffective in ameliorating symptoms and parameters of osteoarthritis. Nevertheless, GlcN has been in long-term use in humans for several decades and induces no relevant side effects aside from occasional allergic reactions.

Short-term administration of high-dose GlcN to model systems or humans acutely impairs glucose metabolism that resembles some of the metabolic features of diabetes mellitus. By contrast, chronic GlcN intake has no detectable influence, or even blood glucose-lowering effects in humans.

Long-term inhibition of glycolysis, by either applying RNA interference (RNAi) to impair expression of glycolytic enzymes, with the application of 2-deoxy-D-glucose (DOG), or by impeding insulin/IGF1 receptor signalling uniformly extends the life span of C. elegans, whereas increased glucose availability reduces nematodal life span. As none of these aforementioned interventions are readily available for use in humans to extend life span, and particularly owing to the fact that DOG unexpectedly shortens life span of rodents, we have now tested whether GlcN could promote healthspan in C. elegans and rodents.

We here find that GlcN inhibits glycolysis to cause an energy deficit that induces mitochondrial biogenesis and alternate fuel use, namely amino-acid oxidation. This is paralleled by an extension of life span in both C. elegans and ageing mice, the latter also showing improved glucose metabolism. These findings implicate that GlcN supplementation may be a versatile approach to delay ageing in humans.

If you dig into the paper, you'll find that life extension in mice is modest, around 10% or so, but pretty consistent judging from the charts. This is for supplementation starting at the two year mark and continuing for another year, by which time only a few mice remained from either group.

For my money an increased knowledge of metabolism and aging is really the only reason to pursue something with such a modest outcome at the dawn of the age of rejuvenation research. The quest for knowledge is a noble thing in and of itself, but don't fool yourself into thinking that this and similar work forms any sort of a road to radical life extension in humans. It does not and cannot. That goal can only come about in the next few decades, soon enough to matter, through growth and development of repair strategies that focus on identifying and repairing the fundamental differences between old tissues and young tissues - a form of research and development that is far, far removed from the paper quoted above.

Comments

Strange take on a pretty impressive paper, e.g., the statement -
"If you dig into the paper, you'll find that life extension in mice is modest, around 10%" - ignores that the glucosamine diet was started late in life (the mouse age equivalent of 65 years), and for the best responders (see graphs in Figure 3) extends lifespan much more than 10%.

The authors of the paper thought the results were good enough to start the regimen themselves. See authors' statements in -
"Could a popular arthritis supplement be the key to a longer life?"
http://www.dailymail.co.uk/health/article-2599894/

I think it is reasonable to wonder whether
- a low caloric, or
- a low carb, or
- a high protein diet, low in methionine (or other essential amino
to reduce either I-GF activity) might enhance the effect further.

Posted by: Lou Pagnucco at April 8th, 2014 8:48 PM

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